OBJECTIVE: To observe the inhibition of resveratrol on coal dust-induced pulmonary fibrosis and explore the possible mechanism. METHODS: A mouse model of pneumoconiosis was established by coal dust inhalation, and resveratrol was administered as treatment. Lung inflammation and fibrosis were observed using hematoxylin/eosin (HE) and Masson staining, and hydroxyproline content was measured by colorimetric assay. In vitro, lung epithelial cells were exposed with coal dust alone or in combination with resveratrol. Cell migration and invasion abilities were assessed using wound healing assay and Transwell assay. The key molecules of epithelial-mesenchymal transition (EMT) were detected by western blotting and ELISA. Additionally, the effects of resveratrol on proliferation and collagen production in TGF-β1-stimulated fibroblasts were examined using EDU, CCK-8, and western blotting. Results: The coal dust group showed marked inflammatory cell infiltration, collagen deposition, and elevated hydroxyproline levels in lung tissue, all of which were significantly improved in the resveratrol-treated group. In vitro, coal dust increased the migration rate, invasive ability, downregulated E-cadherin, and upregulated N-cadherin, vimentin, and Snail of lung epithelial cells, whereas these cellular changes were markedly attenuated in the resveratrol-treated group. Moreover, the levels of TGF-β1 and TNF-α were significantly lower in the resveratrol-treated group than in the coal dust group. In fibroblasts, the cell proliferation rate and collagen (COL-1, COL-3, α-SMA) were lower in the resveratrol-treated group than in the TGF-β1-stimulated group. CONCLUSION: Resveratrol inhibited EMT in lung epithelial cells, reduced TGF-β1 and TNF-α release, suppressed fibroblast-to-myofibroblast transformation (FMT), and alleviated coal dust-induced pulmonary fibrosis.

OBJECTIVE: To observe the inhibition of resveratrol on coal dust-induced pulmonary fibrosis and explore the possible mechanism. METHODS: A mouse model of pneumoconiosis was established by coal dust inhalation, and resveratrol was administered as treatment. Lung inflammation and fibrosis were observed using hematoxylin/eosin (HE) and Masson staining, and hydroxyproline content was measured by colorimetric assay. In vitro, lung epithelial cells were exposed with coal dust alone or in combination with resveratrol. Cell migration and invasion abilities were assessed using wound healing assay and Transwell assay. The key molecules of epithelial-mesenchymal transition (EMT) were detected by western blotting and ELISA. Additionally, the effects of resveratrol on proliferation and collagen production in TGF-β1-stimulated fibroblasts were examined using EDU, CCK-8, and western blotting. Results: The coal dust group showed marked inflammatory cell infiltration, collagen deposition, and elevated hydroxyproline levels in lung tissue, all of which were significantly improved in the resveratrol-treated group. In vitro, coal dust increased the migration rate, invasive ability, downregulated E-cadherin, and upregulated N-cadherin, vimentin, and Snail of lung epithelial cells, whereas these cellular changes were markedly attenuated in the resveratrol-treated group. Moreover, the levels of TGF-β1 and TNF-α were significantly lower in the resveratrol-treated group than in the coal dust group. In fibroblasts, the cell proliferation rate and collagen (COL-1, COL-3, α-SMA) were lower in the resveratrol-treated group than in the TGF-β1-stimulated group. CONCLUSION: Resveratrol inhibited EMT in lung epithelial cells, reduced TGF-β1 and TNF-α release, suppressed fibroblast-to-myofibroblast transformation (FMT), and alleviated coal dust-induced pulmonary fibrosis.

Vincristine (VIN) is a widely used chemotherapeutic agent whose therapeutic application is substantially constrained by concentration-dependent toxicities, including nephrotoxicity. This study aimed to characterize the renoprotective capacity of hesperidin (HES) in a VIN-induced nephrotoxicity model and to delineate the mechanisms underlying its protective action. Twenty-eight female Wistar albino rats were divided into four groups: control, HES (200 mg/kg), VIN (0.17 mg/kg), and VIN (0.17 mg/kg) + HES (200 mg/kg), with all treatments administered for 7 consecutive days. Renal function markers, oxidative stress parameters, apoptosis- and autophagy-related gene expression, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling components, and histopathological alterations were evaluated. VIN administration significantly increased serum urea and creatinine levels, lipid peroxidation, and oxidative DNA damage, while reducing antioxidant defenses (p < 0.05). VIN also induced marked apoptosis, evidenced by increased tumor protein p53 (p53), Bcl-2-associated X protein (Bax), Caspase-3, and C/EBP homologous protein (CHOP) expression and decreased B-cell lymphoma 2 (Bcl-2) levels, together with enhanced autophagy and suppression of PI3K/Akt/mTOR signaling (p < 0.05). These molecular changes were accompanied by severe renal histopathological damage (p < 0.05). HES supplementation significantly attenuated these effects by restoring antioxidant capacity, reducing inflammatory cytokines, suppressing apoptosis, modulating autophagy-related gene expression, and partially restoring PI3K/Akt/mTOR signaling (p < 0.05). Histopathological findings further confirmed the protective effect of HES against VIN-induced renal injury (p < 0.05). In conclusion, HES exerts renoprotective effects against VIN-induced nephrotoxicity by modulating interconnected oxidative stress, inflammation, apoptosis, autophagy, and PI3K/Akt/mTOR signaling pathways, suggesting its potential as a multi-target agent for preventing chemotherapy-associated renal injury in this experimental model.

Vincristine (VIN) is a widely used chemotherapeutic agent whose therapeutic application is substantially constrained by concentration-dependent toxicities, including nephrotoxicity. This study aimed to characterize the renoprotective capacity of hesperidin (HES) in a VIN-induced nephrotoxicity model and to delineate the mechanisms underlying its protective action. Twenty-eight female Wistar albino rats were divided into four groups: control, HES (200 mg/kg), VIN (0.17 mg/kg), and VIN (0.17 mg/kg) + HES (200 mg/kg), with all treatments administered for 7 consecutive days. Renal function markers, oxidative stress parameters, apoptosis- and autophagy-related gene expression, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling components, and histopathological alterations were evaluated. VIN administration significantly increased serum urea and creatinine levels, lipid peroxidation, and oxidative DNA damage, while reducing antioxidant defenses (p < 0.05). VIN also induced marked apoptosis, evidenced by increased tumor protein p53 (p53), Bcl-2-associated X protein (Bax), Caspase-3, and C/EBP homologous protein (CHOP) expression and decreased B-cell lymphoma 2 (Bcl-2) levels, together with enhanced autophagy and suppression of PI3K/Akt/mTOR signaling (p < 0.05). These molecular changes were accompanied by severe renal histopathological damage (p < 0.05). HES supplementation significantly attenuated these effects by restoring antioxidant capacity, reducing inflammatory cytokines, suppressing apoptosis, modulating autophagy-related gene expression, and partially restoring PI3K/Akt/mTOR signaling (p < 0.05). Histopathological findings further confirmed the protective effect of HES against VIN-induced renal injury (p < 0.05). In conclusion, HES exerts renoprotective effects against VIN-induced nephrotoxicity by modulating interconnected oxidative stress, inflammation, apoptosis, autophagy, and PI3K/Akt/mTOR signaling pathways, suggesting its potential as a multi-target agent for preventing chemotherapy-associated renal injury in this experimental model.

Ergothioneine (EGT) is a histidine-derived thiol antioxidant with broad applications in food, pharmaceuticals and cosmetics, but its industrial production is limited by scarce natural sources and low heterologous host titers. Here, a high-yield, methanol-free EGT production platform was established in Pichia pastoris X33 via integrated genetic and process engineering: de novo pathway assembly first generated strain P4 with a shake-flask EGT titer of 99.6 ± 3.2 mg/L via screening of the strong constitutive promoter PGCW14, site-directed engineering of Schizophyllum commune methyltransferase ScEgt1a yielded the V17A mutant, which improved the titer to 188.0 ± 8.6 mg/L in strain P11 alongside accumulated hercynine intermediate, introduction of egtB from Methylobacterium pseudosasicola (encoding the hercynine-to-cys-hercynine conversion enzyme) to drive efficient conversion of the accumulated intermediate produced strain P12 with a titer of 328.2 ± 8.3 mg/L, and further systematic optimization of culture medium and process parameters elevated the final shake-flask EGT titer to 1023.3 ± 17.9 mg/L. This work delivers the first constitutive, methanol-free production strategy for EGT, providing a scalable chassis and transferable integrated genetic-process engineering framework that reaches an advanced level among reported yeast-based EGT production systems, offering a versatile blueprint for sustainable biomanufacture of EGT and other high-value sulfur-containing natural products.

Ergothioneine (EGT) is a histidine-derived thiol antioxidant with broad applications in food, pharmaceuticals and cosmetics, but its industrial production is limited by scarce natural sources and low heterologous host titers. Here, a high-yield, methanol-free EGT production platform was established in Pichia pastoris X33 via integrated genetic and process engineering: de novo pathway assembly first generated strain P4 with a shake-flask EGT titer of 99.6 ± 3.2 mg/L via screening of the strong constitutive promoter PGCW14, site-directed engineering of Schizophyllum commune methyltransferase ScEgt1a yielded the V17A mutant, which improved the titer to 188.0 ± 8.6 mg/L in strain P11 alongside accumulated hercynine intermediate, introduction of egtB from Methylobacterium pseudosasicola (encoding the hercynine-to-cys-hercynine conversion enzyme) to drive efficient conversion of the accumulated intermediate produced strain P12 with a titer of 328.2 ± 8.3 mg/L, and further systematic optimization of culture medium and process parameters elevated the final shake-flask EGT titer to 1023.3 ± 17.9 mg/L. This work delivers the first constitutive, methanol-free production strategy for EGT, providing a scalable chassis and transferable integrated genetic-process engineering framework that reaches an advanced level among reported yeast-based EGT production systems, offering a versatile blueprint for sustainable biomanufacture of EGT and other high-value sulfur-containing natural products.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.

Resveratrol (RSV) is a naturally occurring polyphenolic stilbene that has attracted considerable interest for its biological effects on reproductive health. Drug and chemical-induced reproductive toxicity encompass diverse disturbances that can impair cellular homeostasis, endocrine function, gametogenesis, and reproductive tissue integrity. Available studies indicate that RSV treatment is associated with improved redox balance, reduced inflammatory responses, preservation of cellular and mitochondrial integrity, attenuation of apoptotic signaling, and modulation of steroidogenic and reproductive functions. Nrf2-associated antioxidant responses and SIRT1-related signaling have been reported across several experimental models, while additional findings implicate PI3K/Akt and NF-κB/JNK-c-Jun-associated responses. Ferroptosis, autophagy, and AhR-associated signaling have also emerged as potential contributors in selected models. This review highlights the experimental evidence for RSV in drug- and chemical-induced reproductive toxicity and examines the molecular responses associated with its reported protective effects across diverse experimental models of reproductive injury.

Resveratrol (RSV) is a naturally occurring polyphenolic stilbene that has attracted considerable interest for its biological effects on reproductive health. Drug and chemical-induced reproductive toxicity encompass diverse disturbances that can impair cellular homeostasis, endocrine function, gametogenesis, and reproductive tissue integrity. Available studies indicate that RSV treatment is associated with improved redox balance, reduced inflammatory responses, preservation of cellular and mitochondrial integrity, attenuation of apoptotic signaling, and modulation of steroidogenic and reproductive functions. Nrf2-associated antioxidant responses and SIRT1-related signaling have been reported across several experimental models, while additional findings implicate PI3K/Akt and NF-κB/JNK-c-Jun-associated responses. Ferroptosis, autophagy, and AhR-associated signaling have also emerged as potential contributors in selected models. This review highlights the experimental evidence for RSV in drug- and chemical-induced reproductive toxicity and examines the molecular responses associated with its reported protective effects across diverse experimental models of reproductive injury.

Five sesquiterpenes were isolated from the dried rhizomes of Acorus calamus var. angustatus Besser. Their structures were determined by spectroscopic analysis and ECD calculations, including one new eudesmane-type sesquiterpene, 2-hydroxy-eudesmane K (1), and four known compounds: eudesmane K (2), isocalamendiol (3), aristolone (4), and axinysone B (5). Their neuroprotective activity was evaluated using an Aβ25-35-induced HT22 cell injury model. Compound 1 showed concentration-dependent neuroprotective activity with an EC50 value of 4.64 µM, whereas the EC50 of positive control resveratrol was 3.23 µM. Compounds 2-4 exhibited neuroprotective activity at effective concentrations of 6.25 μM, 3.12-50 μM and 3.12-12.5 μM, while compound 5 showed no obvious protective effect within the tested concentration range. These results indicate that compound 1 represents a potential lead candidate against neurodegenerative diseases, deserving further investigation.

Five sesquiterpenes were isolated from the dried rhizomes of Acorus calamus var. angustatus Besser. Their structures were determined by spectroscopic analysis and ECD calculations, including one new eudesmane-type sesquiterpene, 2-hydroxy-eudesmane K (1), and four known compounds: eudesmane K (2), isocalamendiol (3), aristolone (4), and axinysone B (5). Their neuroprotective activity was evaluated using an Aβ25-35-induced HT22 cell injury model. Compound 1 showed concentration-dependent neuroprotective activity with an EC50 value of 4.64 µM, whereas the EC50 of positive control resveratrol was 3.23 µM. Compounds 2-4 exhibited neuroprotective activity at effective concentrations of 6.25 μM, 3.12-50 μM and 3.12-12.5 μM, while compound 5 showed no obvious protective effect within the tested concentration range. These results indicate that compound 1 represents a potential lead candidate against neurodegenerative diseases, deserving further investigation.

Post-stroke cognitive impairment (PSCI) is a major cause of long-term disability after ischemic stroke, yet its mechanisms remain incompletely explained by infarct volume, lesion location, or conventional vascular risk factors alone. Animal models are indispensable for clarifying how ischemic injury evolves into delayed cognitive dysfunction and for determining which mechanisms are experimentally tractable, reproducible, and translationally relevant. This review examines PSCI from a neurovascular trafficking perspective, focusing on how laboratory animal models can be used to investigate secretory pathway stress, endolysosomal dysfunction, autophagy-lysosomal flux, extracellular vesicle signaling, blood-brain barrier disruption, glial reactivity, myelin debris clearance, white matter injury, and cognition-relevant behavioral phenotypes. Rodent models of transient or permanent middle cerebral artery occlusion, photothrombotic stroke, embolic stroke, chronic cerebral hypoperfusion, bilateral carotid artery stenosis, and subcortical white-matter injury each reproduce selected components of the human PSCI spectrum. No single model fully captures the temporal, vascular, cellular, and cognitive complexity of human PSCI; therefore, model selection should be driven by the mechanistic question, disease phase, vascular pathology, cellular compartment, cognitive domain, and welfare burden under investigation. The central argument is not that neurovascular trafficking failure is already a proven causal pathway, but that well-designed animal studies can test, refine, or falsify this hypothesis. Future studies should integrate model validity, translational rigor, and welfare refinement through longitudinal cognitive testing, multimodal imaging, cell-specific molecular profiling, extracellular vesicle phenotyping, intervention-based validation, randomization, blinding, sample-size justification, humane endpoints, perioperative care, and transparent reporting.

Post-stroke cognitive impairment (PSCI) is a major cause of long-term disability after ischemic stroke, yet its mechanisms remain incompletely explained by infarct volume, lesion location, or conventional vascular risk factors alone. Animal models are indispensable for clarifying how ischemic injury evolves into delayed cognitive dysfunction and for determining which mechanisms are experimentally tractable, reproducible, and translationally relevant. This review examines PSCI from a neurovascular trafficking perspective, focusing on how laboratory animal models can be used to investigate secretory pathway stress, endolysosomal dysfunction, autophagy-lysosomal flux, extracellular vesicle signaling, blood-brain barrier disruption, glial reactivity, myelin debris clearance, white matter injury, and cognition-relevant behavioral phenotypes. Rodent models of transient or permanent middle cerebral artery occlusion, photothrombotic stroke, embolic stroke, chronic cerebral hypoperfusion, bilateral carotid artery stenosis, and subcortical white-matter injury each reproduce selected components of the human PSCI spectrum. No single model fully captures the temporal, vascular, cellular, and cognitive complexity of human PSCI; therefore, model selection should be driven by the mechanistic question, disease phase, vascular pathology, cellular compartment, cognitive domain, and welfare burden under investigation. The central argument is not that neurovascular trafficking failure is already a proven causal pathway, but that well-designed animal studies can test, refine, or falsify this hypothesis. Future studies should integrate model validity, translational rigor, and welfare refinement through longitudinal cognitive testing, multimodal imaging, cell-specific molecular profiling, extracellular vesicle phenotyping, intervention-based validation, randomization, blinding, sample-size justification, humane endpoints, perioperative care, and transparent reporting.

Chronic diabetic glucolipotoxicity is associated with progressive skeletal muscle atrophy, bone loss, cellular senescence, and ferroptotic injury. Because ferroptosis inhibition alone may not restore compromised myogenic capacity, we developed a combined stem cell-conditioning strategy integrating fullerol priming with the stem cell screen-enrich-combine(-biomaterials) circulating system (SECCS). This integrated three-dimensional culture platform uses porous β-TCP granules and intermittent medium circulation to generate BMSCs-derived extracellular vesicles (EVs). Among 2D-EVs, F-2D-EVs, SECCS-EVs, and F-SECCS-EVs, F-SECCS-EVs exhibited the strongest anti-ferroptotic and pro-regenerative effects. In glucolipotoxicity-challenged myoblasts, F-SECCS-EVs attenuated ferroptotic injury and enhanced proliferation and myogenic differentiation. Transcriptomic and functional experiments identified FOXO3 as an important mediator linking antioxidant defense with myogenic programs. In diabetic mice, F-SECCS-EVs improved motor function, muscle strength, myofiber cross-sectional area, and myogenic marker expression while modulating macrophage polarization. Free fullerol, 2D-EVs, and F-2D-EVs produced limited recovery, whereas SECCS-EVs were less effective than F-SECCS-EVs. These muscle benefits were accompanied by favorable changes in tibial bone structure. Collectively, these findings support fullerol-primed SECCS culture as a strategy for coordinating ferroptosis control with myogenic recovery in diabetes-associated musculoskeletal degeneration.

Chronic diabetic glucolipotoxicity is associated with progressive skeletal muscle atrophy, bone loss, cellular senescence, and ferroptotic injury. Because ferroptosis inhibition alone may not restore compromised myogenic capacity, we developed a combined stem cell-conditioning strategy integrating fullerol priming with the stem cell screen-enrich-combine(-biomaterials) circulating system (SECCS). This integrated three-dimensional culture platform uses porous β-TCP granules and intermittent medium circulation to generate BMSCs-derived extracellular vesicles (EVs). Among 2D-EVs, F-2D-EVs, SECCS-EVs, and F-SECCS-EVs, F-SECCS-EVs exhibited the strongest anti-ferroptotic and pro-regenerative effects. In glucolipotoxicity-challenged myoblasts, F-SECCS-EVs attenuated ferroptotic injury and enhanced proliferation and myogenic differentiation. Transcriptomic and functional experiments identified FOXO3 as an important mediator linking antioxidant defense with myogenic programs. In diabetic mice, F-SECCS-EVs improved motor function, muscle strength, myofiber cross-sectional area, and myogenic marker expression while modulating macrophage polarization. Free fullerol, 2D-EVs, and F-2D-EVs produced limited recovery, whereas SECCS-EVs were less effective than F-SECCS-EVs. These muscle benefits were accompanied by favorable changes in tibial bone structure. Collectively, these findings support fullerol-primed SECCS culture as a strategy for coordinating ferroptosis control with myogenic recovery in diabetes-associated musculoskeletal degeneration.

Matrin-3 is a DNA- and RNA-binding protein implicated in cardiovascular development. However, the role of endothelial Matrin-3 in atherosclerosis has not been previously studied. Here, we found that Matrin-3 silencing induces endothelial senescence, characterized by reduced cell proliferation, increased senescence-associated β-galactosidase activity, and impaired mitochondrial function in vitro. Quantitative proteomics and bulk RNA-sequencing identified hundreds of differentially expressed genes and proteins in human endothelial cells. Bioinformatic analyses revealed enrichment of pathways related to DNA replication, p53 signaling, cell-cycle regulation, and cellular senescence. To examine the role of endothelial Matrin-3 in atherosclerosis, we generated Matrin-3 floxed mice on a low-density lipoprotein receptor-knockout background and crossed them with mice carrying an endothelial cell-specific, tamoxifen-inducible Cre driver. In a mouse model of atherosclerosis, endothelial cell-specific Matrin-3 deficiency increased atherosclerotic lesion area by 1.41-fold and was associated with increased plasma low-density lipoprotein cholesterol and triglycerides, increased hepatic cholesterol and triglycerides, and substantial transcriptional alterations in the aortic intima. Endothelial Matrin-3 deficiency also induced hepatic steatosis, fibrosis, inflammation, and endothelial senescence. Single-nucleus RNA-sequencing of the liver further revealed transcriptional reprogramming of hepatocytes, including alterations in pathways related to lipid metabolism, inflammation, and constitutive androstane receptor signaling, consistent with a functional link between endothelial Matrin-3 deficiency and hepatocyte transcriptional responses. Finally, Matrin-3 expression was reduced in mouse and human atherosclerotic plaques. Together, these findings identify endothelial Matrin-3 as an important regulator of endothelial senescence and lipid homeostasis and demonstrate that endothelial Matrin-3 deficiency is associated with both local vascular alterations and systemic metabolic dysfunction in atherosclerosis.

Matrin-3 is a DNA- and RNA-binding protein implicated in cardiovascular development. However, the role of endothelial Matrin-3 in atherosclerosis has not been previously studied. Here, we found that Matrin-3 silencing induces endothelial senescence, characterized by reduced cell proliferation, increased senescence-associated β-galactosidase activity, and impaired mitochondrial function in vitro. Quantitative proteomics and bulk RNA-sequencing identified hundreds of differentially expressed genes and proteins in human endothelial cells. Bioinformatic analyses revealed enrichment of pathways related to DNA replication, p53 signaling, cell-cycle regulation, and cellular senescence. To examine the role of endothelial Matrin-3 in atherosclerosis, we generated Matrin-3 floxed mice on a low-density lipoprotein receptor-knockout background and crossed them with mice carrying an endothelial cell-specific, tamoxifen-inducible Cre driver. In a mouse model of atherosclerosis, endothelial cell-specific Matrin-3 deficiency increased atherosclerotic lesion area by 1.41-fold and was associated with increased plasma low-density lipoprotein cholesterol and triglycerides, increased hepatic cholesterol and triglycerides, and substantial transcriptional alterations in the aortic intima. Endothelial Matrin-3 deficiency also induced hepatic steatosis, fibrosis, inflammation, and endothelial senescence. Single-nucleus RNA-sequencing of the liver further revealed transcriptional reprogramming of hepatocytes, including alterations in pathways related to lipid metabolism, inflammation, and constitutive androstane receptor signaling, consistent with a functional link between endothelial Matrin-3 deficiency and hepatocyte transcriptional responses. Finally, Matrin-3 expression was reduced in mouse and human atherosclerotic plaques. Together, these findings identify endothelial Matrin-3 as an important regulator of endothelial senescence and lipid homeostasis and demonstrate that endothelial Matrin-3 deficiency is associated with both local vascular alterations and systemic metabolic dysfunction in atherosclerosis.

Peripheral nerve injury (PNI) is a common traumatic neurological condition characterized by high rates of disability and poor functional recovery, posing a major global public health and clinical challenge. Currently, clinical practice has established a comprehensive intervention system centered on microsurgical suturing and autologous nerve grafting as core surgical approaches, supplemented by pharmacological treatments such as methylcobalamin, B-complex vitamins, and neurotrophic factors. However, existing treatments can only repair neuroanatomical structures and provide symptomatic support; they struggle to fully restore neural function. Furthermore, there is a lack of effective intervention strategies for chronic neuropathy and neuropathic pain, creating an urgent need to identify multi-target intervention strategies capable of regulating the pathological progression of PNI throughout its entire course. ERK is a core member of the MAPK family, and the Ras/Raf/MEK/ERK signaling cascade it mediates serves as a key hub linking extracellular stimuli to intracellular biological effects. Existing research has confirmed that the ERK signaling pathway is involved in regulating core pathophysiological processes following PNI, including Schwann cell phenotypic transformation, axonal regeneration, neuroinflammatory homeostasis, oxidative stress damage, autophagy regulation, and angiogenesis. This review systematically elucidates the biological basis of the ERK signaling pathway, focuses on its multidimensional and multicellular regulatory mechanisms in PNI repair, and comprehensively summarizes the latest research advances in various intervention strategies targeting the ERK pathway, including small-molecule drugs, natural bioactive compounds, tissue engineering, and physical therapies.

Peripheral nerve injury (PNI) is a common traumatic neurological condition characterized by high rates of disability and poor functional recovery, posing a major global public health and clinical challenge. Currently, clinical practice has established a comprehensive intervention system centered on microsurgical suturing and autologous nerve grafting as core surgical approaches, supplemented by pharmacological treatments such as methylcobalamin, B-complex vitamins, and neurotrophic factors. However, existing treatments can only repair neuroanatomical structures and provide symptomatic support; they struggle to fully restore neural function. Furthermore, there is a lack of effective intervention strategies for chronic neuropathy and neuropathic pain, creating an urgent need to identify multi-target intervention strategies capable of regulating the pathological progression of PNI throughout its entire course. ERK is a core member of the MAPK family, and the Ras/Raf/MEK/ERK signaling cascade it mediates serves as a key hub linking extracellular stimuli to intracellular biological effects. Existing research has confirmed that the ERK signaling pathway is involved in regulating core pathophysiological processes following PNI, including Schwann cell phenotypic transformation, axonal regeneration, neuroinflammatory homeostasis, oxidative stress damage, autophagy regulation, and angiogenesis. This review systematically elucidates the biological basis of the ERK signaling pathway, focuses on its multidimensional and multicellular regulatory mechanisms in PNI repair, and comprehensively summarizes the latest research advances in various intervention strategies targeting the ERK pathway, including small-molecule drugs, natural bioactive compounds, tissue engineering, and physical therapies.

Psoriasis is a chronic inflammatory immune-mediated skin disease with complex pathophysiology, reflecting the need for effective treatment. Commiphora gileadensis (L.) C.Chr. has long been used traditionally for skin disorders; however, its anti-psoriatic potential remains unexplored. This study investigated the GC-MS chemical profile of C. gileadensis hydro-distilled essential oil from its aerial parts, revealing sabinene and viridiflorol as the major compounds. Nanoemulgel formulations of the oil (Eg: 0.25%, 0.5%, and 1% w/w) were evaluated in an imiquimod (IMQ)-induced psoriasis-like model in BALB/c mice. Treatment with Eg significantly decreased the psoriasis area and severity index and spleen index in a dose-dependent manner, with the highest efficacy at 1%. It exhibited antioxidant properties by increasing glutathione and decreasing malondialdehyde, and an anti-inflammatory effect by inhibiting the phosphorylated nuclear factor-κB and inflammatory interleukins IL-17, IL-23, IL-1β, and IL-18. It attenuated tissue pyroptosis and restored cellular autophagy, supported by histopathology and reduced Ki67 expression. These findings highlight nanoemulgel of C. gileadensis essential oil as a potential therapy to alleviate psoriasis.

Psoriasis is a chronic inflammatory immune-mediated skin disease with complex pathophysiology, reflecting the need for effective treatment. Commiphora gileadensis (L.) C.Chr. has long been used traditionally for skin disorders; however, its anti-psoriatic potential remains unexplored. This study investigated the GC-MS chemical profile of C. gileadensis hydro-distilled essential oil from its aerial parts, revealing sabinene and viridiflorol as the major compounds. Nanoemulgel formulations of the oil (Eg: 0.25%, 0.5%, and 1% w/w) were evaluated in an imiquimod (IMQ)-induced psoriasis-like model in BALB/c mice. Treatment with Eg significantly decreased the psoriasis area and severity index and spleen index in a dose-dependent manner, with the highest efficacy at 1%. It exhibited antioxidant properties by increasing glutathione and decreasing malondialdehyde, and an anti-inflammatory effect by inhibiting the phosphorylated nuclear factor-κB and inflammatory interleukins IL-17, IL-23, IL-1β, and IL-18. It attenuated tissue pyroptosis and restored cellular autophagy, supported by histopathology and reduced Ki67 expression. These findings highlight nanoemulgel of C. gileadensis essential oil as a potential therapy to alleviate psoriasis.

INTRODUCTION: Repurposing inexpensive oral compounds targeting metabolic reprogramming is a pragmatic strategy. CURGET is a five-node oral regimen designed to induce metabolic starvation in tumors. AREAS COVERED: Comprehensive literature search. The malignant phenotype features concurrent upregulation of glycolysis (HK2), glutaminolysis (GLS1), de novo lipogenesis (FASN), the mevalonate pathway (HMGR), and fatty-acid β-oxidation (FAO/3-KAT). CURGET combines four widely available polyphenols and a common cardiac drug: curcumin, urolithin A, resveratrol, EGCG, and trimetazidine to target these five enzymes. Additional mechanisms include context-dependent pro-oxidant activity and epigenetic modulation such as DNMT, HDAC, and HAT inhibition linked to cofactor depletion. This review synthesizes human safety and pharmacokinetic data, plasma AUC overlap with in vitro inhibitory concentrations, knockout evidence of metabolic plasticity, and clinical co-expression of HK2, GLS1, and FASN. EXPERT OPINION: CURGET represents a coherent, low-cost oral strategy rather than a finalized protocol. Key priorities include developing bioavailable formulations, conducting preclinical studies with defined metabolic endpoints, and early-phase pharmacokinetic and safety assessments of the combination. If CURGET shows a favorable therapeutic index, it may be most applicable to metabolically characterized tumors, including gastric, pancreatic, and selected breast cancers. Successful development could improve access to affordable metabolic adjuncts and help reduce global disparities in cancer care.

INTRODUCTION: Repurposing inexpensive oral compounds targeting metabolic reprogramming is a pragmatic strategy. CURGET is a five-node oral regimen designed to induce metabolic starvation in tumors. AREAS COVERED: Comprehensive literature search. The malignant phenotype features concurrent upregulation of glycolysis (HK2), glutaminolysis (GLS1), de novo lipogenesis (FASN), the mevalonate pathway (HMGR), and fatty-acid β-oxidation (FAO/3-KAT). CURGET combines four widely available polyphenols and a common cardiac drug: curcumin, urolithin A, resveratrol, EGCG, and trimetazidine to target these five enzymes. Additional mechanisms include context-dependent pro-oxidant activity and epigenetic modulation such as DNMT, HDAC, and HAT inhibition linked to cofactor depletion. This review synthesizes human safety and pharmacokinetic data, plasma AUC overlap with in vitro inhibitory concentrations, knockout evidence of metabolic plasticity, and clinical co-expression of HK2, GLS1, and FASN. EXPERT OPINION: CURGET represents a coherent, low-cost oral strategy rather than a finalized protocol. Key priorities include developing bioavailable formulations, conducting preclinical studies with defined metabolic endpoints, and early-phase pharmacokinetic and safety assessments of the combination. If CURGET shows a favorable therapeutic index, it may be most applicable to metabolically characterized tumors, including gastric, pancreatic, and selected breast cancers. Successful development could improve access to affordable metabolic adjuncts and help reduce global disparities in cancer care.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with impaired granulosa cell (GC) glycolytic activity. Although lactate dehydrogenase A (LDHA)-a key glycolytic enzyme modulated by acetylation-is involved, its regulatory mechanism remains unclear. This study investigated whether nicotinamide mononucleotide (NMN) alleviates PCOS by promoting LDHA deacetylation to enhance glycolytic function. METHODS: We established a PCOS rat model via letrozole (1 mg/kg/d) gavage combined with high-fat diet for 30 days; after successful modeling, rats were randomly assigned to receive either vehicle or NMN (500 mg/kg/d) for an additional 30 days..We then evaluated metabolic phenotypes, reproductive hormone profiles, ovarian histopathology, and estrous cycle regularity. The underlying molecular mechanism was verified in testosterone (10 μM)-treated human granulosa-like KGN cells via a series of molecular assays including qRT-PCR, western blotting, co-immunoprecipitation (Co-IP), and site-directed mutagenesis. RESULTS: NMN supplementation significantly reversed insulin resistance, hyperandrogenism, estrous cycle disorder, and polycystic ovarian morphology in PCOS rats, and simultaneously increased ovarian NAD+ levels and glycolytic activity. We further identified SIRT2 as the specific deacetylase of LDHA, and uncovered K119 as the key functional acetylation site that regulates LDHA enzymatic activity. Mechanistically, NMN promoted SIRT2-mediated deacetylation of LDHA at K119, which enhanced glycolytic activity, promoted proliferation, and inhibited apoptosis in ovarian GCs. CONCLUSION: Our findings demonstrate that NMN enhances glycolytic activity in ovarian GCs via the SIRT2/LDHA-K119 regulatory axis, thereby ameliorating PCOS-related reproductive and metabolic disorders. Collectively, these findings identify the SIRT2-LDHA axis as a novel therapeutic target and provide preclinical evidence supporting NMN as a potential intervention for PCOS.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with impaired granulosa cell (GC) glycolytic activity. Although lactate dehydrogenase A (LDHA)-a key glycolytic enzyme modulated by acetylation-is involved, its regulatory mechanism remains unclear. This study investigated whether nicotinamide mononucleotide (NMN) alleviates PCOS by promoting LDHA deacetylation to enhance glycolytic function. METHODS: We established a PCOS rat model via letrozole (1 mg/kg/d) gavage combined with high-fat diet for 30 days; after successful modeling, rats were randomly assigned to receive either vehicle or NMN (500 mg/kg/d) for an additional 30 days..We then evaluated metabolic phenotypes, reproductive hormone profiles, ovarian histopathology, and estrous cycle regularity. The underlying molecular mechanism was verified in testosterone (10 μM)-treated human granulosa-like KGN cells via a series of molecular assays including qRT-PCR, western blotting, co-immunoprecipitation (Co-IP), and site-directed mutagenesis. RESULTS: NMN supplementation significantly reversed insulin resistance, hyperandrogenism, estrous cycle disorder, and polycystic ovarian morphology in PCOS rats, and simultaneously increased ovarian NAD+ levels and glycolytic activity. We further identified SIRT2 as the specific deacetylase of LDHA, and uncovered K119 as the key functional acetylation site that regulates LDHA enzymatic activity. Mechanistically, NMN promoted SIRT2-mediated deacetylation of LDHA at K119, which enhanced glycolytic activity, promoted proliferation, and inhibited apoptosis in ovarian GCs. CONCLUSION: Our findings demonstrate that NMN enhances glycolytic activity in ovarian GCs via the SIRT2/LDHA-K119 regulatory axis, thereby ameliorating PCOS-related reproductive and metabolic disorders. Collectively, these findings identify the SIRT2-LDHA axis as a novel therapeutic target and provide preclinical evidence supporting NMN as a potential intervention for PCOS.

Penthorum chinense Pursh is a traditional medicinal and edible plant rich in flavonoids and complex polyphenols. Evaluating its aqueous extracts against foodborne pathogens via biomass assay, microplate spread tests and scanning electron microscopy revealed distinct tissue-specific efficacies: leaf and stem extracts exhibited strong bactericidal effects (16-128 mg/mL), notably against Bacillus cereus, whereas flower extracts demonstrated potent biofilm inhibition (IC50 < 1 mg/mL). Broad-coverage UPLC-ESI-Q-TOF-MS metabolite profiling annotated 93 compounds, and integration with Random Forest nested cross-validation prioritised candidate constituents associated with the measured activities. While confirming established antimicrobials (gallic acid, pinocembrin, pinostrobin, (-)-epicatechin gallate, afzelechin, corilagin, and hydrolysable derivatives of quercetin, kaempferol, and liquiritin) as major active constituents, our ML model first revealed several unreported bioactive compounds. Specifically, turmeronol A, vanillic acid glucoside, lotaustralin, and 2',6'-dihydroxydihydrochalcone-4'-O-(3''-O-galloyl)-β-D-glucopyranoside act as crucial bactericidal agents, while Gemin D, lamiophlomiol C, 4'-hydroxyflavanone, and pinocembrin-7-O-[4,6-HHDP]-glucoside primarily contribute to anti-biofilm efficacy. Finally, their multi-target mechanisms were preliminarily explored.

Penthorum chinense Pursh is a traditional medicinal and edible plant rich in flavonoids and complex polyphenols. Evaluating its aqueous extracts against foodborne pathogens via biomass assay, microplate spread tests and scanning electron microscopy revealed distinct tissue-specific efficacies: leaf and stem extracts exhibited strong bactericidal effects (16-128 mg/mL), notably against Bacillus cereus, whereas flower extracts demonstrated potent biofilm inhibition (IC50 < 1 mg/mL). Broad-coverage UPLC-ESI-Q-TOF-MS metabolite profiling annotated 93 compounds, and integration with Random Forest nested cross-validation prioritised candidate constituents associated with the measured activities. While confirming established antimicrobials (gallic acid, pinocembrin, pinostrobin, (-)-epicatechin gallate, afzelechin, corilagin, and hydrolysable derivatives of quercetin, kaempferol, and liquiritin) as major active constituents, our ML model first revealed several unreported bioactive compounds. Specifically, turmeronol A, vanillic acid glucoside, lotaustralin, and 2',6'-dihydroxydihydrochalcone-4'-O-(3''-O-galloyl)-β-D-glucopyranoside act as crucial bactericidal agents, while Gemin D, lamiophlomiol C, 4'-hydroxyflavanone, and pinocembrin-7-O-[4,6-HHDP]-glucoside primarily contribute to anti-biofilm efficacy. Finally, their multi-target mechanisms were preliminarily explored.

BACKGROUND: Chronic low-grade inflammation and oxidative stress are hallmarks of metabolic disorders. A naturally occurring polyphenol, resveratrol (RSV), has shown promise in modulating these pathways, however clinical evidence is mixed. To systematically review and perform a dose-response meta-analysis of randomized controlled trials (RCTs) to assess the effects of RSV supplementation on inflammatory and oxidative stress biomarkers in patients with these disorders. METHODS: A systematic search up to August 2026 following PRISMA guidelines was conducted to identify RCTs that examined the effect of RSV on inflammatory (including C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)) and oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC)) biomarkers in populations with metabolic disorders. Random effects models were used to combine the data. Dose-response relationships were evaluated using linear and non-linear modelling. Trial sequential analysis (TSA) was performed to adjust for repetitive testing, calculate the required information size (RIS), and assess the robustness of the cumulative evidence. RESULTS: Meta-analysis of 25 RCTs for CRP showed a statistically significant reduction (SMD = -0.18, 95% CI: -0.33 to -0.03, p = 0.0202, I2 = 20%), while IL-6 and TNF-α showed non-significant changes with high heterogeneity. Regarding oxidative stress markers, no significant overall effects were observed for CAT, MDA, or SOD. Analysis of TAC showed a non-significant trend (SMD = 0.63, 95% CI: -0.08 to 1.33, p = 0.0668, I2 = 58.5%), which became statistically significant only after the exclusion of one influential outlier trial (SMD = 0.83, 95% CI: 0.23 to 1.44, p = 0.0273, I2 = 0%). TSA crossed the monitoring boundary for CRP, supporting an anti-inflammatory effect, while evidence for other biomarkers remained inconclusive. Dose-response meta-analyses identified no significant linear or non-linear associations between daily RSV dosage and inflammatory outcomes. CONCLUSION: RSV supplementation is associated with a modest reduction in CRP, supported by TSA; however, effects on other inflammatory and oxidative stress biomarkers were null or inconclusive. The absence of a clear dose-response relationship and the surrogate status of CRP limit the clinical interpretability of these findings.

BACKGROUND: Chronic low-grade inflammation and oxidative stress are hallmarks of metabolic disorders. A naturally occurring polyphenol, resveratrol (RSV), has shown promise in modulating these pathways, however clinical evidence is mixed. To systematically review and perform a dose-response meta-analysis of randomized controlled trials (RCTs) to assess the effects of RSV supplementation on inflammatory and oxidative stress biomarkers in patients with these disorders. METHODS: A systematic search up to August 2026 following PRISMA guidelines was conducted to identify RCTs that examined the effect of RSV on inflammatory (including C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)) and oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC)) biomarkers in populations with metabolic disorders. Random effects models were used to combine the data. Dose-response relationships were evaluated using linear and non-linear modelling. Trial sequential analysis (TSA) was performed to adjust for repetitive testing, calculate the required information size (RIS), and assess the robustness of the cumulative evidence. RESULTS: Meta-analysis of 25 RCTs for CRP showed a statistically significant reduction (SMD = -0.18, 95% CI: -0.33 to -0.03, p = 0.0202, I2 = 20%), while IL-6 and TNF-α showed non-significant changes with high heterogeneity. Regarding oxidative stress markers, no significant overall effects were observed for CAT, MDA, or SOD. Analysis of TAC showed a non-significant trend (SMD = 0.63, 95% CI: -0.08 to 1.33, p = 0.0668, I2 = 58.5%), which became statistically significant only after the exclusion of one influential outlier trial (SMD = 0.83, 95% CI: 0.23 to 1.44, p = 0.0273, I2 = 0%). TSA crossed the monitoring boundary for CRP, supporting an anti-inflammatory effect, while evidence for other biomarkers remained inconclusive. Dose-response meta-analyses identified no significant linear or non-linear associations between daily RSV dosage and inflammatory outcomes. CONCLUSION: RSV supplementation is associated with a modest reduction in CRP, supported by TSA; however, effects on other inflammatory and oxidative stress biomarkers were null or inconclusive. The absence of a clear dose-response relationship and the surrogate status of CRP limit the clinical interpretability of these findings.

BACKGROUND: Calcium oxalate (CaOx) stones are the most prevalent urological calculi with high incidence and recurrence. Effective preventive drugs remain lacking because of unclear pathogenesis. Although the imbalance of the dual renin-angiotensin system (RAS) axes is closely linked to oxidative stress and autophagy, its role in CaOx stone formation remains undefined. METHODS: In vitro, human renal tubular epithelial cells were stimulated with CaOx crystals, with siRNA-mediated AT1R or MasR knockdown or pretreatment with Ang Ⅱ, Ang-(1-7), antioxidant Nacetylcysteine (NAC) or autophagy inhibitor 3-methyladenine (3-MA). RAS components, oxidative stress markers, autophagy-related proteins, stone-related proteins and crystal adhesion were detected. In vivo, a mouse CaOx stone model was induced by intraperitoneal glyoxylic acid injection, with adeno-associated virus-mediated AT1R or MasR knockdown. The above indicators and renal crystal deposition were evaluated. RESULTS: CaOx crystals significantly activated the ACE/Ang Ⅱ/AT1R axis and inhibited the ACE2/Ang-(1-7)/MasR axis in vitro and in vivo, causing intrarenal RAS imbalance. CaOx crystals induced NOX2/4-mediated oxidative stress and AMPK/mTOR-dependent autophagy, which formed a mutually reinforcing loop to upregulate stone-related proteins (OPN, CD44, MCP-1). Activating the ACE/Ang Ⅱ/AT1R axis with Ang Ⅱ exacerbated these pathological changes, while AT1R knockdown alleviated them; conversely, activating the ACE2/Ang-(1-7)/MasR axis with Ang-(1-7) exerted protective effects, whereas MasR knockdown worsened injury. In vivo findings corroborated these results. CONCLUSION: The ACE/Ang Ⅱ/AT1R axis plays a pathogenic role in CaOx stone formation, whereas the ACE2/Ang-(1-7)/MasR axis exerts a protective effect. Restoring this intrarenal RAS balance represents a promising therapeutic strategy against CaOx stones.

BACKGROUND: Calcium oxalate (CaOx) stones are the most prevalent urological calculi with high incidence and recurrence. Effective preventive drugs remain lacking because of unclear pathogenesis. Although the imbalance of the dual renin-angiotensin system (RAS) axes is closely linked to oxidative stress and autophagy, its role in CaOx stone formation remains undefined. METHODS: In vitro, human renal tubular epithelial cells were stimulated with CaOx crystals, with siRNA-mediated AT1R or MasR knockdown or pretreatment with Ang Ⅱ, Ang-(1-7), antioxidant Nacetylcysteine (NAC) or autophagy inhibitor 3-methyladenine (3-MA). RAS components, oxidative stress markers, autophagy-related proteins, stone-related proteins and crystal adhesion were detected. In vivo, a mouse CaOx stone model was induced by intraperitoneal glyoxylic acid injection, with adeno-associated virus-mediated AT1R or MasR knockdown. The above indicators and renal crystal deposition were evaluated. RESULTS: CaOx crystals significantly activated the ACE/Ang Ⅱ/AT1R axis and inhibited the ACE2/Ang-(1-7)/MasR axis in vitro and in vivo, causing intrarenal RAS imbalance. CaOx crystals induced NOX2/4-mediated oxidative stress and AMPK/mTOR-dependent autophagy, which formed a mutually reinforcing loop to upregulate stone-related proteins (OPN, CD44, MCP-1). Activating the ACE/Ang Ⅱ/AT1R axis with Ang Ⅱ exacerbated these pathological changes, while AT1R knockdown alleviated them; conversely, activating the ACE2/Ang-(1-7)/MasR axis with Ang-(1-7) exerted protective effects, whereas MasR knockdown worsened injury. In vivo findings corroborated these results. CONCLUSION: The ACE/Ang Ⅱ/AT1R axis plays a pathogenic role in CaOx stone formation, whereas the ACE2/Ang-(1-7)/MasR axis exerts a protective effect. Restoring this intrarenal RAS balance represents a promising therapeutic strategy against CaOx stones.

Chemotherapy-induced nephrotoxicity remains a major dose-limiting complication in cancer treatment. Accumulating evidence indicates that renal injury triggered by agents such as cisplatin, doxorubicin, methotrexate, and cyclophosphamide is primarily mediated by interconnected mechanisms including oxidative stress, mitochondrial dysfunction, inflammatory signaling, and apoptosis. Despite advances in supportive care, effective nephroprotective strategies remain limited. This review provides a comprehensive mechanistic synthesis of current preclinical evidence regarding the nephroprotective potential of berberine, a bioactive isoquinoline alkaloid. Rather than acting as a single-pathway antioxidant, berberine appears to exert pleiotropic cytoprotective effects through coordinated modulation of multiple signaling networks. These include activation of the Nrf2/Keap1 antioxidant defense system; regulation of autophagy and mitophagy via the AMPK/mTOR and PINK1/Parkin pathways; suppression of inflammatory cascades such as HMGB1/TLR4/RAGE, NF-κB, and MAPK signaling; and inhibition of mitochondrial-dependent apoptotic pathways through modulation of p53 and the Bax/Bcl-2 axis. By integrating these interconnected mechanisms, berberine restores redox homeostasis, preserves mitochondrial integrity, attenuates inflammatory amplification, and prevents tubular cell death. Collectively, the available evidence positions berberine as a promising multi-target adjunct candidate for mitigating chemotherapy-associated renal injury. However, clinical validation and pharmacokinetic optimization remain essential for translational application.

Chemotherapy-induced nephrotoxicity remains a major dose-limiting complication in cancer treatment. Accumulating evidence indicates that renal injury triggered by agents such as cisplatin, doxorubicin, methotrexate, and cyclophosphamide is primarily mediated by interconnected mechanisms including oxidative stress, mitochondrial dysfunction, inflammatory signaling, and apoptosis. Despite advances in supportive care, effective nephroprotective strategies remain limited. This review provides a comprehensive mechanistic synthesis of current preclinical evidence regarding the nephroprotective potential of berberine, a bioactive isoquinoline alkaloid. Rather than acting as a single-pathway antioxidant, berberine appears to exert pleiotropic cytoprotective effects through coordinated modulation of multiple signaling networks. These include activation of the Nrf2/Keap1 antioxidant defense system; regulation of autophagy and mitophagy via the AMPK/mTOR and PINK1/Parkin pathways; suppression of inflammatory cascades such as HMGB1/TLR4/RAGE, NF-κB, and MAPK signaling; and inhibition of mitochondrial-dependent apoptotic pathways through modulation of p53 and the Bax/Bcl-2 axis. By integrating these interconnected mechanisms, berberine restores redox homeostasis, preserves mitochondrial integrity, attenuates inflammatory amplification, and prevents tubular cell death. Collectively, the available evidence positions berberine as a promising multi-target adjunct candidate for mitigating chemotherapy-associated renal injury. However, clinical validation and pharmacokinetic optimization remain essential for translational application.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is driven by lipid overload and inflammatory activation of Kupffer cells (KCs). Xanthoangelol (XAG), a major chalcone in Angelica keiskei Koidzumi, has anti-inflammatory activity, but its effects on KC immunometabolic dysfunction remain unclear. OBJECTIVE: To determine whether XAG-enriched A. keiskei extract ameliorates MASLD by targeting foamy KC dysfunction. METHODS: MASLD was induced in male C57BL/6 N mice by fast-food diet feeding for 15 weeks, followed by daily oral administration of XAG-enriched A. keiskei extract for a further 9 weeks. Liver injury, steatosis, collagen deposition, inflammatory signaling, and KC abundance were evaluated. Primary hepatocytes, primary KCs, immortalized KCs, and reporter macrophages were used to define cell-specific responses, and KC-to-hepatocyte crosstalk was assessed by conditioned-medium transfer. MASH-like KC dysfunction was modeled using palmitic acid, oleic acid, LPS, glucose, fructose, and TGF-β with or without XAG. RNA sequencing, pathway enrichment, immunoblotting, RT-qPCR, and immunofluorescence were used to assess inflammatory, lipid-handling, autophagy-lysosome, and TFEB-CLEAR pathways. RESULTS: XAG-enriched A. keiskei extract reduced FFD-induced liver injury, steatosis, collagen deposition, metabolic dysfunction, inflammatory signaling, and KC accumulation. Primary hepatocytes showed limited responses in the lipid-related endpoints examined, whereas KCs exhibited pronounced inflammatory and immunometabolic responses to XAG. In MASH-stimulated KCs, XAG suppressed NF-κB/MAPK-associated inflammatory activation, reduced lipid accumulation, attenuated NLRP3 inflammasome signaling, and activated autophagy-lysosome and lipid-clearance programs. Mechanistically, XAG promoted TFEB nuclear localization and increased CLEAR network gene expression. CONCLUSION: XAG-enriched A. keiskei extract ameliorates experimental MASLD by suppressing foamy KC inflammatory activation and enhancing TFEB-CLEAR-associated lysosomal regulation, supporting XAG as a KC-directed immunomodulatory candidate.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is driven by lipid overload and inflammatory activation of Kupffer cells (KCs). Xanthoangelol (XAG), a major chalcone in Angelica keiskei Koidzumi, has anti-inflammatory activity, but its effects on KC immunometabolic dysfunction remain unclear. OBJECTIVE: To determine whether XAG-enriched A. keiskei extract ameliorates MASLD by targeting foamy KC dysfunction. METHODS: MASLD was induced in male C57BL/6 N mice by fast-food diet feeding for 15 weeks, followed by daily oral administration of XAG-enriched A. keiskei extract for a further 9 weeks. Liver injury, steatosis, collagen deposition, inflammatory signaling, and KC abundance were evaluated. Primary hepatocytes, primary KCs, immortalized KCs, and reporter macrophages were used to define cell-specific responses, and KC-to-hepatocyte crosstalk was assessed by conditioned-medium transfer. MASH-like KC dysfunction was modeled using palmitic acid, oleic acid, LPS, glucose, fructose, and TGF-β with or without XAG. RNA sequencing, pathway enrichment, immunoblotting, RT-qPCR, and immunofluorescence were used to assess inflammatory, lipid-handling, autophagy-lysosome, and TFEB-CLEAR pathways. RESULTS: XAG-enriched A. keiskei extract reduced FFD-induced liver injury, steatosis, collagen deposition, metabolic dysfunction, inflammatory signaling, and KC accumulation. Primary hepatocytes showed limited responses in the lipid-related endpoints examined, whereas KCs exhibited pronounced inflammatory and immunometabolic responses to XAG. In MASH-stimulated KCs, XAG suppressed NF-κB/MAPK-associated inflammatory activation, reduced lipid accumulation, attenuated NLRP3 inflammasome signaling, and activated autophagy-lysosome and lipid-clearance programs. Mechanistically, XAG promoted TFEB nuclear localization and increased CLEAR network gene expression. CONCLUSION: XAG-enriched A. keiskei extract ameliorates experimental MASLD by suppressing foamy KC inflammatory activation and enhancing TFEB-CLEAR-associated lysosomal regulation, supporting XAG as a KC-directed immunomodulatory candidate.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Its pathogenesis involves mutant huntingtin aggregation, impaired proteostasis and autophagy, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, neuroinflammation and progressive neuronal loss. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, has demonstrated antioxidant, anti-inflammatory, proteostasis-modulating and stress-response effects in experimental studies. In a transgenic HD mouse model, WA-induced heat-shock-response activation was associated with reduced mutant huntingtin aggregation and attenuation of selected disease-related abnormalities. In contrast, evidence for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation, autophagy regulation, mitochondrial protection and suppression of inflammatory signaling is derived predominantly from cellular experiments and non-HD neurological or inflammatory models rather than from validated HD models. The direct relevance of these proposed mechanisms to HD therefore remains to be established. No clinical studies have demonstrated the safety or therapeutic efficacy of WA in individuals with HD. Moreover, its bioavailability, pharmacokinetic behavior, optimal dose, long-term toxicity, central nervous system exposure and possible drug interactions remain insufficiently characterized. This review critically evaluates HD-specific and indirect evidence concerning the neuroprotective actions of WA, identifies important methodological and translational limitations and discusses priorities for future investigation. Current evidence supports WA as an experimental compound for further preclinical study rather than as an established or clinically applicable treatment for HD.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Its pathogenesis involves mutant huntingtin aggregation, impaired proteostasis and autophagy, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, neuroinflammation and progressive neuronal loss. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, has demonstrated antioxidant, anti-inflammatory, proteostasis-modulating and stress-response effects in experimental studies. In a transgenic HD mouse model, WA-induced heat-shock-response activation was associated with reduced mutant huntingtin aggregation and attenuation of selected disease-related abnormalities. In contrast, evidence for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation, autophagy regulation, mitochondrial protection and suppression of inflammatory signaling is derived predominantly from cellular experiments and non-HD neurological or inflammatory models rather than from validated HD models. The direct relevance of these proposed mechanisms to HD therefore remains to be established. No clinical studies have demonstrated the safety or therapeutic efficacy of WA in individuals with HD. Moreover, its bioavailability, pharmacokinetic behavior, optimal dose, long-term toxicity, central nervous system exposure and possible drug interactions remain insufficiently characterized. This review critically evaluates HD-specific and indirect evidence concerning the neuroprotective actions of WA, identifies important methodological and translational limitations and discusses priorities for future investigation. Current evidence supports WA as an experimental compound for further preclinical study rather than as an established or clinically applicable treatment for HD.

BACKGROUND: Chronic inflammation exerts paradoxical effects in breast cancer, inducing growth arrest while sustaining tumor progression. However, how autocrine and paracrine inflammatory cytokine induced senescence integrates with tumor-promoting behaviour remains unclear. Here, we identify a reciprocal IL-1β/IL-6 circuit that links inflammatory cues, epigenetic remodeling and cytokine induced senescence in luminal breast cancer cells. METHODS: Following treatment with IL-1β and IL-6, MCF-7 cells were examined using cell-cycle, apoptosis, reactive oxygen species flow cytometry assays, and senescence assays; RNA sequencing; global DNA methylation quantification; methylation-specific PCR; ChIP-qPCR for histone marks; cytokine ELISA; and western blotting for DNMTs and STAT3/AKT/NF-κB signaling proteins. The kinetics of IL-1β and IL-6 signaling were examined using receptor antagonism and pharmacological inhibition. RESULTS: IL-1β induced senescence characterized by G0/G1 arrest, elevated SA-β-gal activity, ROS accumulation and absence of apoptosis. Transcriptomic profiling revealed cell-cycle regulator repression, enrichment of senescence-associated signatures and a pro-inflammatory secretory phenotype. Mechanistically, IL-1β induced increased DNMT1 and DNMT3A expression, elevated global DNA methylation, induced promoter-specific DNA methylation (IL-15, HMGB2) and histone mark remodeling (IL-6, IL1RN, BCL2,BAX) at inflammatory, senescence, and apoptotic loci. IL-1 receptor antagonism attenuated these effects. IL-6 induced downstream of IL-1β, in turn activated STAT3, increased DNMT1 and DNMT3B expression, amplified IL-1β expression and tumor-promoting phenotypes, while sustaining the IL-1β induced senescence state. IL-6R blockade disrupted this axis and reduced tumor-promoting effects. CONCLUSION: An IL-1β/IL-6 inflammatory loop drives epigenetic remodeling associated with cytokine induced senescence while promoting tumor-supportive signaling. IL-1β initiates the senescence program, whereas IL-6 reinforces and sustains this state through STAT3/DNMT signaling, highlighting inflammatory cytokine signaling pathways as potential therapeutic targets for breast cancer therapy.

BACKGROUND: Chronic inflammation exerts paradoxical effects in breast cancer, inducing growth arrest while sustaining tumor progression. However, how autocrine and paracrine inflammatory cytokine induced senescence integrates with tumor-promoting behaviour remains unclear. Here, we identify a reciprocal IL-1β/IL-6 circuit that links inflammatory cues, epigenetic remodeling and cytokine induced senescence in luminal breast cancer cells. METHODS: Following treatment with IL-1β and IL-6, MCF-7 cells were examined using cell-cycle, apoptosis, reactive oxygen species flow cytometry assays, and senescence assays; RNA sequencing; global DNA methylation quantification; methylation-specific PCR; ChIP-qPCR for histone marks; cytokine ELISA; and western blotting for DNMTs and STAT3/AKT/NF-κB signaling proteins. The kinetics of IL-1β and IL-6 signaling were examined using receptor antagonism and pharmacological inhibition. RESULTS: IL-1β induced senescence characterized by G0/G1 arrest, elevated SA-β-gal activity, ROS accumulation and absence of apoptosis. Transcriptomic profiling revealed cell-cycle regulator repression, enrichment of senescence-associated signatures and a pro-inflammatory secretory phenotype. Mechanistically, IL-1β induced increased DNMT1 and DNMT3A expression, elevated global DNA methylation, induced promoter-specific DNA methylation (IL-15, HMGB2) and histone mark remodeling (IL-6, IL1RN, BCL2,BAX) at inflammatory, senescence, and apoptotic loci. IL-1 receptor antagonism attenuated these effects. IL-6 induced downstream of IL-1β, in turn activated STAT3, increased DNMT1 and DNMT3B expression, amplified IL-1β expression and tumor-promoting phenotypes, while sustaining the IL-1β induced senescence state. IL-6R blockade disrupted this axis and reduced tumor-promoting effects. CONCLUSION: An IL-1β/IL-6 inflammatory loop drives epigenetic remodeling associated with cytokine induced senescence while promoting tumor-supportive signaling. IL-1β initiates the senescence program, whereas IL-6 reinforces and sustains this state through STAT3/DNMT signaling, highlighting inflammatory cytokine signaling pathways as potential therapeutic targets for breast cancer therapy.

Impaired mitophagy is a core driver of acute kidney injury (AKI), yet effective pharmacological strategies to restore this mitochondrial quality control mechanism remain limited. Paeoniflorin (Pae), a natural monoterpene glycoside, has shown renoprotective potential, but whether and how it regulates mitophagy remain unclear.. This study investigated the protective effects of Pae in mice subjected to bilateral renal ischaemia-reperfusion injury (IRI) and in cisplatin-treated TCMK-1 cells, with renal tubular-specific Prdx5 conditional knockout (Prdx5-CKO) mice used to determine the requirement for PRDX5. Pae treatment dose-dependently ameliorated renal tubular injury, reduced serum creatinine and BUN levels and inflammatory cytokine expression, and restored mitochondrial DNA copy number.Mechanistically, Pae upregulated PRDX5, which interacted with and negatively regulated RACK1. PRDX5 deficiency abolished the protective effects of Pae, aggravated renal injury, and further suppressed PINK1/Parkin expression. Conversely, RACK1 overexpression suppressed PINK1/Parkin and induced cellular injury, while RACK1 knockdown restored mitophagy and alleviated cisplatin-induced damage. Critically, the renoprotective effect of Pae was strictly PRDX5-dependent, as RACK1 knockdown rescued Pae efficacy in PRDX5-deficient cells. These findings demonstrate that Pae alleviates AKI by activating PINK1/Parkin-mediated mitophagy through the PRDX5/RACK1 signalling axis, identifying PRDX5 as an indispensable therapeutic target and revealing a novel mechanism for maintaining mitochondrial homeostasis in AKI.

Impaired mitophagy is a core driver of acute kidney injury (AKI), yet effective pharmacological strategies to restore this mitochondrial quality control mechanism remain limited. Paeoniflorin (Pae), a natural monoterpene glycoside, has shown renoprotective potential, but whether and how it regulates mitophagy remain unclear.. This study investigated the protective effects of Pae in mice subjected to bilateral renal ischaemia-reperfusion injury (IRI) and in cisplatin-treated TCMK-1 cells, with renal tubular-specific Prdx5 conditional knockout (Prdx5-CKO) mice used to determine the requirement for PRDX5. Pae treatment dose-dependently ameliorated renal tubular injury, reduced serum creatinine and BUN levels and inflammatory cytokine expression, and restored mitochondrial DNA copy number.Mechanistically, Pae upregulated PRDX5, which interacted with and negatively regulated RACK1. PRDX5 deficiency abolished the protective effects of Pae, aggravated renal injury, and further suppressed PINK1/Parkin expression. Conversely, RACK1 overexpression suppressed PINK1/Parkin and induced cellular injury, while RACK1 knockdown restored mitophagy and alleviated cisplatin-induced damage. Critically, the renoprotective effect of Pae was strictly PRDX5-dependent, as RACK1 knockdown rescued Pae efficacy in PRDX5-deficient cells. These findings demonstrate that Pae alleviates AKI by activating PINK1/Parkin-mediated mitophagy through the PRDX5/RACK1 signalling axis, identifying PRDX5 as an indispensable therapeutic target and revealing a novel mechanism for maintaining mitochondrial homeostasis in AKI.

Obesity and its associated metabolic disorders have become major global public health challenges. Increasing evidence indicates that mitophagy plays a pivotal role in the pathogenesis of obesity and related metabolic diseases. This study aimed to investigate the role and underlying mechanisms of E3 ubiquitin ligase RNF126 in obesity and non-alcoholic fatty liver disease (NAFLD). Using Rnf126+/- mice fed a high-fat diet (HFD), we found RNF126 deficiency markedly exacerbated body weight gain, elevated serum ALT and AST levels, inflammatory responses, apoptosis, and insulin resistance. Histological analysis with H&E and Oil Red O staining revealed that RNF126 deficiency aggravated hepatic inflammatory cell infiltration, lipid droplet accumulation, and adipocyte hypertrophy in HFD-fed mice. HFD feeding significantly inhibited RNF126 expression in liver and muscle. Moreover, Rnf126+/- mice exhibited reduced oxygen consumption, carbon dioxide production and heat generation without changes in food intake. Mechanistically, qPCR and Western blot analyses demonstrated that RNF126 deficiency suppressed the mRNA and protein expression of UCP-1, SIRT1, and PGC-1α in the liver and white adipose tissue, indicating impaired mitochondrial biogenesis. Moreover, the protein levels of cleaved PINK1, Parkin, and LC3 were reduced, while p62 expression was increased in the liver of Rnf126+/- mice, indicating inhibited autophagic activity. Consistently, oxidative stress was significantly elevated, as evidenced by increased MDA levels and decreased SOD and GSH contents. Rnf126+/- mice livers displayed obvious mitochondrial swelling and partial cristae disorganization with an increase of mtDNA expression. Mitochondrial complex-III enzymatic activity, hepatic ATP, TOM20 protein expression and complex-III subunit UQCRFS1 expression were substantially decreased in HFD-fed Rnf126+/- mice. At the cellular level, RNF126 overexpression in palmitic acid-treated HepG2 cells restored cleaved PINK1, Parkin, and LC3 protein levels, while reducing p62 expression, indicating that RNF126 promotes mitophagy. Furthermore, ROS fluorescence assays showed that RNF126 overexpression attenuated intracellular ROS accumulation. Rescue experiments demonstrated that the protective effects of RNF126 on mitochondrial membrane potential, lipid accumulation, and mitophagy marker expression are dependent on its ubiquitin ligase activity. Overall, RNF126 alleviates HFD-induced lipid accumulation and hepatic injury by promoting mitophagy and maintaining redox homeostasis, suggesting its potential as a novel therapeutic target for NAFLD.

Obesity and its associated metabolic disorders have become major global public health challenges. Increasing evidence indicates that mitophagy plays a pivotal role in the pathogenesis of obesity and related metabolic diseases. This study aimed to investigate the role and underlying mechanisms of E3 ubiquitin ligase RNF126 in obesity and non-alcoholic fatty liver disease (NAFLD). Using Rnf126+/- mice fed a high-fat diet (HFD), we found RNF126 deficiency markedly exacerbated body weight gain, elevated serum ALT and AST levels, inflammatory responses, apoptosis, and insulin resistance. Histological analysis with H&E and Oil Red O staining revealed that RNF126 deficiency aggravated hepatic inflammatory cell infiltration, lipid droplet accumulation, and adipocyte hypertrophy in HFD-fed mice. HFD feeding significantly inhibited RNF126 expression in liver and muscle. Moreover, Rnf126+/- mice exhibited reduced oxygen consumption, carbon dioxide production and heat generation without changes in food intake. Mechanistically, qPCR and Western blot analyses demonstrated that RNF126 deficiency suppressed the mRNA and protein expression of UCP-1, SIRT1, and PGC-1α in the liver and white adipose tissue, indicating impaired mitochondrial biogenesis. Moreover, the protein levels of cleaved PINK1, Parkin, and LC3 were reduced, while p62 expression was increased in the liver of Rnf126+/- mice, indicating inhibited autophagic activity. Consistently, oxidative stress was significantly elevated, as evidenced by increased MDA levels and decreased SOD and GSH contents. Rnf126+/- mice livers displayed obvious mitochondrial swelling and partial cristae disorganization with an increase of mtDNA expression. Mitochondrial complex-III enzymatic activity, hepatic ATP, TOM20 protein expression and complex-III subunit UQCRFS1 expression were substantially decreased in HFD-fed Rnf126+/- mice. At the cellular level, RNF126 overexpression in palmitic acid-treated HepG2 cells restored cleaved PINK1, Parkin, and LC3 protein levels, while reducing p62 expression, indicating that RNF126 promotes mitophagy. Furthermore, ROS fluorescence assays showed that RNF126 overexpression attenuated intracellular ROS accumulation. Rescue experiments demonstrated that the protective effects of RNF126 on mitochondrial membrane potential, lipid accumulation, and mitophagy marker expression are dependent on its ubiquitin ligase activity. Overall, RNF126 alleviates HFD-induced lipid accumulation and hepatic injury by promoting mitophagy and maintaining redox homeostasis, suggesting its potential as a novel therapeutic target for NAFLD.

Osteoarthritis (OA) is a chronic, degenerative disease affecting joint tissue. Resveratrol (RES), a natural polyphenolic compound, has anti‑inflammatory, antioxidant and anti‑apoptotic effects in chondrocytes and macrophages, suggesting therapeutic potential for OA. The present study investigated the molecular mechanisms of RES in OA treatment through network pharmacology analysis and in vitro and in vivo experiments. Network pharmacology was performed to identify potential therapeutic targets and pathways. An OA cell model was established by treating SW1353 cells with IL‑1β, followed by RES intervention without or with AMPK inhibitor to evaluate the effects on the AMPK/PPARγ signaling pathway, NLRP3 inflammasome response, and extracellular matrix (ECM) metabolism. For in vivo assays, OA mice were established through the destabilization of the medial meniscus (DMM) surgery, and administered RES through oral gavage. Histopathological changes, serum inflammatory factors and the expression of target proteins in articular cartilage were analyzed. Network pharmacology identified the AMPK/PPARγ pathway as a key mechanism underlying the therapeutic effects of RES in OA. In vitro, RES activated the AMPK/PPARγ pathway and inhibited the NLRP3 inflammasome response, thereby preserving ECM homeostasis in SW1353 cells. In vivo, RES alleviated OA progression by suppressing cartilage degeneration and synovitis, and regulating serum inflammatory levels. The target protein changes were consistent with the in vitro findings. The present study demonstrates that RES effectively regulates the NLRP3 inflammasome response by activating the AMPK/PPARγ signaling pathway, providing a valuable experimental foundation and potential clinical utility for RES as a complementary and alternative therapy for OA.

Osteoarthritis (OA) is a chronic, degenerative disease affecting joint tissue. Resveratrol (RES), a natural polyphenolic compound, has anti‑inflammatory, antioxidant and anti‑apoptotic effects in chondrocytes and macrophages, suggesting therapeutic potential for OA. The present study investigated the molecular mechanisms of RES in OA treatment through network pharmacology analysis and in vitro and in vivo experiments. Network pharmacology was performed to identify potential therapeutic targets and pathways. An OA cell model was established by treating SW1353 cells with IL‑1β, followed by RES intervention without or with AMPK inhibitor to evaluate the effects on the AMPK/PPARγ signaling pathway, NLRP3 inflammasome response, and extracellular matrix (ECM) metabolism. For in vivo assays, OA mice were established through the destabilization of the medial meniscus (DMM) surgery, and administered RES through oral gavage. Histopathological changes, serum inflammatory factors and the expression of target proteins in articular cartilage were analyzed. Network pharmacology identified the AMPK/PPARγ pathway as a key mechanism underlying the therapeutic effects of RES in OA. In vitro, RES activated the AMPK/PPARγ pathway and inhibited the NLRP3 inflammasome response, thereby preserving ECM homeostasis in SW1353 cells. In vivo, RES alleviated OA progression by suppressing cartilage degeneration and synovitis, and regulating serum inflammatory levels. The target protein changes were consistent with the in vitro findings. The present study demonstrates that RES effectively regulates the NLRP3 inflammasome response by activating the AMPK/PPARγ signaling pathway, providing a valuable experimental foundation and potential clinical utility for RES as a complementary and alternative therapy for OA.

Non‑small cell lung cancer (NSCLC) remains a leading cause of cancer‑associated mortality and urgently requires new therapeutic agents. In the present study, phenotypic screening of natural herbal extracts was performed, identifying Disporum cantoniense extract as a selective inhibitor of NSCLC cell viability. Bioactivity‑guided fractionation further revealed that the petroleum ether fraction (DPF) was the major active fraction. DPF suppressed the viability, proliferation, colony formation, migration and invasion of A549 and H1299 cells while exhibiting weaker cytotoxicity toward BEAS‑2B cells. In addition, DPF increased propidium iodide (PI)‑positive cell death and lactate dehydrogenase release in NSCLC cells, indicating that DPF‑induced viability loss was accompanied by membrane‑damaging cytotoxicity. Transcriptomic and network pharmacology analyses indicated significant enrichment of autophagy‑, apoptosis‑, AMPK‑, mTOR‑, and MAPK‑associated pathways. Mechanistically, DPF increased LC3‑II accumulation, promoted green fluorescent protein‑LC3 puncta formation and autophagic flux, and activated the AMPK/mTOR/unc‑51 like autophagy activating kinase 1 and MEK/ERK signaling pathways. DPF also induced apoptosis, as demonstrated by increased Annexin V positivity, elevated cleaved caspase‑3 and Bax expression, reduced Bcl‑2 expression, and reduced cytotoxicity in Bax‑Bak double‑knockout mouse embryonic fibroblast (MEF) cells. Notably, pharmacological inhibition of autophagy or its upstream regulators attenuated DPF‑induced cytotoxicity. In addition, autophagy‑deficient Atg7‑/‑ MEF cells exhibited reduced DPF‑induced PI‑positive cell death, loss of cell viability, and caspase‑3 activation, further supporting the involvement of Atg7‑dependent autophagy in DPF‑induced apoptosis. In a xenograft model, DPF significantly inhibited tumor growth and increased apoptosis‑ and autophagy‑associated markers in tumor tissues without evident systemic toxicity. Collectively, these findings identify DPF as a principal anti‑NSCLC fraction of Disporum cantoniense and suggest that it suppresses NSCLC progression through AMPK/mTOR/unc‑51 like autophagy activating kinase 1‑ and MEK/ERK‑mediated autophagy‑dependent apoptosis.

Non‑small cell lung cancer (NSCLC) remains a leading cause of cancer‑associated mortality and urgently requires new therapeutic agents. In the present study, phenotypic screening of natural herbal extracts was performed, identifying Disporum cantoniense extract as a selective inhibitor of NSCLC cell viability. Bioactivity‑guided fractionation further revealed that the petroleum ether fraction (DPF) was the major active fraction. DPF suppressed the viability, proliferation, colony formation, migration and invasion of A549 and H1299 cells while exhibiting weaker cytotoxicity toward BEAS‑2B cells. In addition, DPF increased propidium iodide (PI)‑positive cell death and lactate dehydrogenase release in NSCLC cells, indicating that DPF‑induced viability loss was accompanied by membrane‑damaging cytotoxicity. Transcriptomic and network pharmacology analyses indicated significant enrichment of autophagy‑, apoptosis‑, AMPK‑, mTOR‑, and MAPK‑associated pathways. Mechanistically, DPF increased LC3‑II accumulation, promoted green fluorescent protein‑LC3 puncta formation and autophagic flux, and activated the AMPK/mTOR/unc‑51 like autophagy activating kinase 1 and MEK/ERK signaling pathways. DPF also induced apoptosis, as demonstrated by increased Annexin V positivity, elevated cleaved caspase‑3 and Bax expression, reduced Bcl‑2 expression, and reduced cytotoxicity in Bax‑Bak double‑knockout mouse embryonic fibroblast (MEF) cells. Notably, pharmacological inhibition of autophagy or its upstream regulators attenuated DPF‑induced cytotoxicity. In addition, autophagy‑deficient Atg7‑/‑ MEF cells exhibited reduced DPF‑induced PI‑positive cell death, loss of cell viability, and caspase‑3 activation, further supporting the involvement of Atg7‑dependent autophagy in DPF‑induced apoptosis. In a xenograft model, DPF significantly inhibited tumor growth and increased apoptosis‑ and autophagy‑associated markers in tumor tissues without evident systemic toxicity. Collectively, these findings identify DPF as a principal anti‑NSCLC fraction of Disporum cantoniense and suggest that it suppresses NSCLC progression through AMPK/mTOR/unc‑51 like autophagy activating kinase 1‑ and MEK/ERK‑mediated autophagy‑dependent apoptosis.