Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Extracellular lactate reprograms mitochondrial metabolism and NAD/NADH redox balance in blood-brain barrier endothelial cells via an LDHB-MPC-NAD axis.
Jain C, Kuzmychova H, Grewal A … +6 more , Chawla U, Mukherjee R, Banerji V, Anderson CM, Martell E, Sharif T
Free Radic Biol Med · 2026 May · PMID 42217683 · Publisher ↗
Brain endothelial cells (BECs) form the structural foundation of the blood-brain barrier (BBB) and exhibit a paradoxical metabolic phenotype, converting approximately 90% of consumed glucose to lactate despite residing i...
Brain endothelial cells (BECs) form the structural foundation of the blood-brain barrier (BBB) and exhibit a paradoxical metabolic phenotype, converting approximately 90% of consumed glucose to lactate despite residing in an oxygen-rich vascular environment. Whether the extracellular lactate that BECs continuously produce and export feeds back to regulate their own metabolism and redox state has not been directly investigated. Here, using validated BBB model, we demonstrate that exogenous lactate drives a concentration- and time-dependent biphasic growth response, with 10 mM lactate maximally promoting BEC proliferation at 48 h. Mechanistically, lactate suppresses canonical glycolysis evidenced by downregulation of GLUT1 and key glycolytic enzymes and reduced glucose uptake while simultaneously driving a coordinated shift toward mitochondrial oxidative metabolism. This shift is mediated by upregulation of LDHB, MPC1, MPC2, and PDH activation, enabling lactate-derived pyruvate to enter mitochondria and fuel comprehensive TCA cycle engagement, mitochondrial biogenesis, and enhanced oxidative phosphorylation capacity as measured by high-resolution respirometry. At the redox level, lactate oxidation imposes reductive pressure on the NAD/NADH pool, which is counterbalanced by activation of the NAMPT-dependent NAD salvage pathway, resulting in expansion of the total NAD pool. Genetic silencing of LDHB or MPC1 and pharmacological inhibition of NAMPT each independently abolish lactate-driven BEC proliferation, establishing the LDHB-MPC-NAD axis as mechanistically essential. These findings identify the cerebrovascular endothelium as an active participant in brain lactate mitochondrial function and introduce the LDHB-MPC-NAD axis as a novel redox-metabolic regulatory circuit at the BBB.
Bushen Tiaojing decoction ameliorates meiotic impairment to improve oocyte quality during aging through blocking the iron overload-induced p53/CDK1/ESPL1 pathway.
Li L, Xi Y, Li J … +8 more , Feng S, Chen C, Liu Q, Wu S, Zhang Y, Sun Y, He M, Du H
Free Radic Biol Med · 2026 May · PMID 42214643 · Publisher ↗
The decline in oocyte quality is a key factor contributing to the age-related deterioration of female fertility. In women of advanced maternal age, impaired oocyte development is primarily manifested as meiotic abnormali...
The decline in oocyte quality is a key factor contributing to the age-related deterioration of female fertility. In women of advanced maternal age, impaired oocyte development is primarily manifested as meiotic abnormalities. An important underlying pathological mechanism is mitochondrial dysfunction, which is often associated with iron overload during aging. Previous studies have suggested that the traditional Chinese medicine formula Bushen Tiaojing Decoction (BSTJD) may improve oocyte quality; however, its specific protective effects in women of advanced maternal age and the related mechanisms remain unclear. This study aimed to investigate whether BSTJD ameliorates meiotic defects in oocytes from aged mice by inhibiting aging-related iron overload. We established both naturally aged and FeSO-induced iron overload mouse models, followed by BSTJD intervention. In vitro experiments, oocytes from aged mice were cultured and treated with BSTJD-containing serum or adenovirus infection. The results indicated that BSTJD may improve oocyte quality under advanced maternal age conditions by inhibiting iron overload and enhancing mitochondrial function. BSTJD suppressed iron overload-induced reactive oxygen species accumulation, thereby downregulating p53 and p21 expression, promoting CDK1 expression, and reducing ESPL1 expression. Through this regulatory mechanism, BSTJD prevented premature cleavage of chromosomal cohesin by ESPL1, thereby supporting the normal completion of meiosis in aged oocytes and reducing the occurrence of spindle abnormalities and aneuploidy. This study suggests that BSTJD may improve oocyte quality in aged mice by inhibiting iron overload and its downstream p53/CDK1/ESPL1 signaling pathway. This work provides experimental evidence for the clinical application of BSTJD and offers a potential target for intervention strategies aimed at improving oocyte quality decline in women of advanced maternal age.
TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
Li Z, Tang Y, Zhang D … +6 more , Li J, Wang T, Pan Q, Meng X, Tian X, Deng H
Free Radic Biol Med · 2026 May · PMID 42214642 · Publisher ↗
Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to...
Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) level, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.
MCT1-mediated lactate transport regulates ferroptosis in ulcerative colitis via histone lactylation.
Yan J, Wu Y, Guo Y … +5 more , Liu J, Shen C, Wang R, Jiang X, Wang L
Free Radic Biol Med · 2026 May · PMID 42214641 · Publisher ↗
Ferroptosis, an iron-dependent type of controlled cell death caused by lipid peroxidation, contributes to intestinal epithelial injury in ulcerative colitis (UC). Monocarboxylate transporter 1 (MCT1) is a major monocarbo...
Ferroptosis, an iron-dependent type of controlled cell death caused by lipid peroxidation, contributes to intestinal epithelial injury in ulcerative colitis (UC). Monocarboxylate transporter 1 (MCT1) is a major monocarboxylate transporter in cells that regulates monocarboxylate metabolism in epithelial cells. However, its importance in the intestine and the underlying mechanisms are largely unknown. This study revealed that MCT1 is strongly associated with the degree of ferroptosis in individuals with colitis, and the potential mechanism through which MCT1 regulates ferroptosis caused by colonic damage was explored. In vivo, MCT1 inhibitors, exogenous lactate, and GPR81 knockout mice were used to investigate the underlying mechanism of MCT1-mediated lactate shuttling in DSS-induced colitis. To investigate the mechanism of MCT1 in TNF-α-induced ferroptosis, cells were subjected to MCT1 overexpression, treated with the ferroptosis inhibitor ferrostatin-1 (Fer-1), or exposed to lactate for 0, 4, 8, 12, 24, or 36 h. The results revealed that MCT1 expression was downregulated in UC patients and mouse models and was correlated with increased ferroptosis. MCT1 overexpression reduced epithelial ferroptosis in vitro, whereas MCT1 inhibition exacerbated it. Lactate treatment had the greatest protective effect at 8 h (when GPX4 expression peaked). Mechanistically, extracellular lactate activates a protective GPR81/cluster of differentiation 147 (CD147) negative feedback loop to promote the translocation of MCT1 from the cytoplasm to the plasma membrane, enhancing lactate uptake. Genetic ablation of GPR81 or inhibition of MCT1 abolished this protective feedback loop. The accumulation of intracellular lactate then promotes histone H4 lysine 16 lactylation (H4K16la). Coimmunoprecipitation (co-IP) revealed that TNF-α decreased the binding between GCN5 and H4K16la, whereas lactate therapy increased this interaction. This lactylation enhances the activity of xCT, leading to increased gene expression. This study reveals a novel MCT1-lactate-epigenetic axis that mitigates UC-related ferroptosis through feedback regulation, highlighting the critical time-dependent effect of lactate.
S-Nitrosylation of TRAP1 drives the progression of HFpEF through activation of the Rb-E2F axis in cardiomyocytes.
Dong Y, Zhu Y, Huang Y … +6 more , Xiang C, Zhao W, Hua Y, Chen Y, Chen Q, Zhang F
Free Radic Biol Med · 2026 May · PMID 42214640 · Publisher ↗
RATIONALE: Heart failure with preserved ejection fraction (HFpEF) arises from comorbidity-driven meta-inflammation and nitrosative stress, yet how these insults reprogram cardiomyocyte growth control remains unclear. We...
RATIONALE: Heart failure with preserved ejection fraction (HFpEF) arises from comorbidity-driven meta-inflammation and nitrosative stress, yet how these insults reprogram cardiomyocyte growth control remains unclear. We hypothesized that inducible nitric oxide synthase (iNOS)-dependent S-nitrosylation (SNO) of tumor necrosis factor receptor-associated protein 1 (TRAP1) activates E2F-driven hypertrophic programs by remodeling the retinoblastoma protein (Rb)-E2F signaling axis. METHODS: Biotin-switch assays were used to quantify TRAP1-specific S-nitrosylation (SNO-TRAP1) in hearts from mice subjected to a two-hit HFpEF model (high-fat diet + Nω-nitro-L-arginine methyl ester (L-NAME), 12 weeks) and chow controls, as well as in cardiomyocytes, endothelial cells, and fibroblasts isolated by Langendorff perfusion. Causality was tested using pharmacological iNOS inhibition and cardiomyocyte-targeted expression of TRAP1 wild type or a S-nitrosylation cysteine 501 (Cys501) mutant. TRAP1-Rb-E2F interactions were examined using co-immunoprecipitation, domain mapping, transcriptional reporter assays, and complementary protein-protein docking analyses. RESULTS: TRAP1 S-nitrosylation was markedly increased in HFpEF hearts, with enrichment in cardiomyocytes, and correlated with diastolic dysfunction and cardiac hypertrophy. Short-term iNOS inhibition improved diastolic indices and attenuated hypertrophic remodeling. Cardiomyocyte-specific expression of the TRAP1 Cys501A mutant reduced SNO-TRAP1 and alleviated HFpEF-like phenotypes. Mechanistically, Rb was identified as a novel TRAP1-interacting partner. SNO-TRAP1 enhanced TRAP1-Rb association while disrupting Rb-E2F binding, leading to increased E2F transcriptional activity independently of Rb phosphorylation. CONCLUSIONS: An iNOS-SNO-TRAP1-Rb-E2F axis drives cardiomyocyte hypertrophy and diastolic dysfunction in HFpEF via phosphorylation-independent displacement of E2F from Rb. Targeting nitrosative stress or preventing TRAP1 Cys501 S-nitrosylation engagement may offer mechanism-based therapies for HFpEF.
Spatial multi-omics reveals region-specific redox dysregulation in chronic aristolochic acid I-induced nephrotoxicity.
Cai D, Cheng S, Lan T … +6 more , Zhang X, Zhang X, Ma X, Jin H, Abliz Z, Wang Z
Free Radic Biol Med · 2026 May · PMID 42208666 · Publisher ↗
Aristolochic acid I (AAI) is a potent nephrotoxin responsible for aristolochic acid nephropathy (AAN); however, the spatial relationship between toxicant accumulation and region-specific metabolic dysfunction during chro...
Aristolochic acid I (AAI) is a potent nephrotoxin responsible for aristolochic acid nephropathy (AAN); however, the spatial relationship between toxicant accumulation and region-specific metabolic dysfunction during chronic exposure remains incompletely understood. Here, we established a 12-week chronic AAN rat model using repeated oral administration of AAI (1 and 10 mg/kg/day) and integrated spatial metabolomics, spatial transcriptomics, and regional LC-MS/MS quantification to elucidate the underlying mechanisms. Quantitative analysis revealed dose-dependent accumulation of aristolactam I (ALI), the major Phase I metabolite, predominantly in cortical regions. Airflow-assisted desorption electrospray ionization (AFADESI)-MSI uncovered extensive, region-specific metabolic reprogramming, with the inner cortex exhibiting the greatest perturbation. Integrated analyses demonstrated coordinated disruption of arginine-nitric oxide signaling, mitochondrial oxidative phosphorylation, fatty acid β-oxidation, arachidonic acid-mediated inflammation, purine metabolism, antioxidant defense, and osmolyte homeostasis. Spatial transcriptomics further revealed suppression of redox-regulating enzymes, fatty acid oxidation pathways, and transporters, alongside activation of oxidative stress and inflammatory responses. Mechanistically, chronic AAI exposure induced mitochondrial dysfunction, glutathione depletion, lipid peroxidation, and energy insufficiency, establishing spatially localized redox stress microdomains. The strong spatial concordance between ALI accumulation and metabolic collapse supports a toxicokinetic-toxicodynamic coupling in AAN pathogenesis. Collectively, this study provides a spatially resolved multi-omics framework that advances mechanistic understanding of AAI-induced nephrotoxicity and identifies potential targets for intervention.
Sustained human C-peptide protects against retinal neurodegeneration via PEDF restoration and oxidative stress inhibition in a mouse model of age-related macular degeneration.
Koh TY, Cho WR, Jeon HY … +4 more , Moon CH, Yoon JS, Kim M, Ha KS
Free Radic Biol Med · 2026 May · PMID 42203079 · Publisher ↗
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly. The molecular events that initiate retinal degeneration in dry AMD remain incompletely understood, and effective thera...
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly. The molecular events that initiate retinal degeneration in dry AMD remain incompletely understood, and effective therapeutic options are limited. Here, we investigated the therapeutic potential of K9-C-peptide against sodium iodate (NaIO)-induced retinal neurodegeneration and explored its underlying molecular mechanisms. K9-C-peptide markedly attenuated NaIO-induced retinal apoptosis, thinning, and structural disruption. These protective effects were accompanied by significant suppression of ROS generation, decreased expression of pro-inflammatory cytokines, and inhibition of reactive gliosis. Mechanistically, K9-C-peptide restored NaIO-induced downregulation of pigment epithelium-derived factor (PEDF). Consistently, intravitreal administration of hydrogel-formulated PEDF similarly reduced oxidative stress and retinal degeneration, supporting a central role for PEDF in mediating the protective effects of K9-C-peptide. Both K9-C-peptide and PEDF improved impaired axonal transport, further confirming their neuroprotective efficacy. Notably, sustained intraocular delivery of human C-peptide or PEDF conferred robust protection against NaIO-induced retinal neurodegeneration for at least three weeks following a single administration. These findings suggest that K9-C-peptide may serve as a long-acting therapeutic candidate that targets early oxidative and inflammatory events, potentially through PEDF restoration, in NaIO-induced retinal degeneration. This study provides mechanistic insight into the antioxidative and anti-inflammatory actions of C-peptide-based therapy in dry AMD-like pathology.
Empagliflozin mitigates doxorubicin-induced cardiac dysfunction in association with preserved t-tubule integrity and improved Ca handling: a structural mechanistic insight.
Lin R, Li Y, Liu X … +11 more , Meng F, Wang X, Peng X, Jiang T, Liu C, Jin S, Liu T, Ruan Y, Bai R, Liu N, Dong J
Free Radic Biol Med · 2026 May · PMID 42203078 · Publisher ↗
BACKGROUND: Clinical and experimental studies have suggested that sodium-glucose cotransporter type-2 inhibitors (SGLT2i) may exert a preventive effect against doxorubicin (Dox)-induced heart failure; however, the underl...
BACKGROUND: Clinical and experimental studies have suggested that sodium-glucose cotransporter type-2 inhibitors (SGLT2i) may exert a preventive effect against doxorubicin (Dox)-induced heart failure; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate whether empagliflozin (Emp) protects against Dox-induced cardiotoxicity by preserving transverse tubule (t-tubule) structure and improving Ca handling. METHODS: Adult male C57BL/6 mice were randomly assigned to four groups: Control, Emp-only, Dox-only, and Dox+ Emp. Emp was administered to the Emp-only and Dox+ Emp groups at 10 mg/kg/day, and Dox was administered to the Dox-only and Dox+ Emp groups at a cumulative dose of 15 mg/kg. Cardiac function was assessed by echocardiography. T-tubule ultrastructure and Ca handling were evaluated using confocal microscopy and IonOptix imaging. Protein expression was analyzed by western blotting. RESULTS: Dox-treated mice exhibited increased left ventricular dilatation and impaired cardiac function, both of which were attenuated in the Dox + Emp group. Dox induced blunted and dyssynchronous sarcoplasmic reticulum Ca release, characterized by reduced amplitude and delayed Ca transients, as well as increased Ca spark frequency. These abnormalities were significantly ameliorated by Emp treatment. In addition, Emp effectively prevented Dox-induced t-tubule loss and disorganization. Emp also ameliorated Dox-induced alterations in JPH2, BIN1, Ca/calmodulin-dependent protein kinase II (CaMKII), and CaMKII-dependent phosphorylation of RyR2, leading to improved synchronous Ca release, enhanced Ca transient amplitude, and reduced Ca sparks frequency. CONCLUSIONS: Dox-induced cardiotoxicity is associated with severe t-tubule remodeling and impaired Ca-handling. Emp prevents Dox-induced structural and functional remodeling of t-tubule and improves Ca-handling, thereby exerting cardioprotective effects in mice. These findings provide structural-level mechanistic insight into Emp-mediated cardioprotection and support the potential of Emp as a preventive strategy against Dox-induced cardiotoxicity.
Redox-sensitive mA epitranscriptomic remodeling in cadmium stress and toxicity.
Niu S, Wāng Y
Free Radic Biol Med · 2026 May · PMID 42191043 · Publisher ↗
Environmental stressors that disrupt redox homeostasis pose a significant threat to metabolic balance, tissue integrity, and organismal development. Increasing evidence identifies N-methyladenosine (mA), a dynamic and st...
Environmental stressors that disrupt redox homeostasis pose a significant threat to metabolic balance, tissue integrity, and organismal development. Increasing evidence identifies N-methyladenosine (mA), a dynamic and stress-responsive RNA modification, as a central regulator that translates oxidative cues into functional changes in RNA metabolism and cellular behavior. Redox imbalance can recalibrate the activity, localization, and substrate selectivity of mA writers, erasers, and readers, thereby reshaping transcriptomic programs that control inflammation, antioxidant defense, proteostasis, mitochondrial quality, and stress-adaptive cell fate decisions. These mA-dependent responses manifest across diverse tissues, including the liver, kidney, pancreas, lung, brain, and reproductive organs, where they influence unfolded protein responses, β-cell resilience, epithelial plasticity, fibrotic remodeling, neurodegenerative processes, and gametogenic stability. mA dysregulation also contributes to placental stress signaling, developmental vulnerability, and intergenerational transmission of metabolic and reproductive outcomes following environmental perturbation. In this work, we integrate emerging evidence to propose a unified framework illustrating how redox-sensitive mA signaling orchestrates cellular and physiological responses to environmental stress, using cadmium as an exemplar due to its well-established role as an oxidative stress inducer. We highlight mechanistic convergence across tissues, note sources of exposure specificity, and discuss technological advances that are redefining the resolution of mA mapping. Finally, we outline opportunities for leveraging mA as a biomarker, mechanistic probe, and potential therapeutic target in the study of environmental cadmium stress and associated diseases.
NOX4 signatures in human abdominal aortic aneurysm reveal links to vascular cell plasticity, extracellular matrix remodeling and inflammation.
Sinha A, Kapalla M, Schürmann C … +14 more , Busch A, Tabac R, Mittag J, Hamann B, Sabater-Lleal M, Müglich M, Kopaliani I, Poitz DM, Jänichen C, Bundschuh RA, Klimova A, Reeps C, Schröder K, Hofmann A
Free Radic Biol Med · 2026 May · PMID 42191042 · Publisher ↗
BACKGROUND: NADPH-oxidase 4 (NOX4) is the predominant isoform of NADPH oxidases in the vasculature. While global deletion of NOX4 protects against abdominal aortic aneurysm (AAA) formation in mice, cell-specific overexpr...
BACKGROUND: NADPH-oxidase 4 (NOX4) is the predominant isoform of NADPH oxidases in the vasculature. While global deletion of NOX4 protects against abdominal aortic aneurysm (AAA) formation in mice, cell-specific overexpression promotes disease development. However, the cellular sources of NOX4 and the associated transcriptional programs in human AAA remain incompletely understood. METHODS: NOX4 was investigated using single-cell RNA sequencing and histopathological analyses of AAA tissue. RESULTS: NOX4 mRNA expression was comparable between ruptured AAA (rAAA) and electively treated AAA (eAAA) and did not correlate with AAA size, AAA volume, or thickness of the intraluminal thrombus. In human AAA, NOX4 expression correlated with markers of inflammatory signaling, extracellular matrix (ECM) remodeling, and antioxidant responses, while showing an inverse relationship with the endothelial marker CD31. Single-cell RNA sequencing revealed predominant NOX4 expression in fibroblasts and smooth muscle cells (SMCs). In these populations, higher NOX4 levels were associated with transcriptional programs related to ECM synthesis and remodeling, SMC phenotypic modulation, myofibroblast differentiation, and pathways involved in proliferation, migration, and redox metabolism. Notably, NOX4 SMCs were enriched for proteoglycan biosynthesis pathways, whereas NOX4 fibroblasts were associated with iron ion transport processes. In contrast, NOX4 expression was low in endothelial cells (ECs), and pseudotime analysis suggested a transition from ECs toward myofibroblast-like states accompanied by increased NOX4 expression, consistent with endothelial-to-mesenchymal transition. CONCLUSION: In human AAA, NOX4 is primarily expressed in fibroblasts and SMCs and is associated with transcriptional programs linked to inflammation, ECM remodeling, and cellular phenotype modulation. These findings indicate that NOX4 reflects disease activity and vascular remodeling rather than AAA size and highlight NOX4 as a potential target for cell type-specific therapeutic strategies in AAA.
YY1 Promotes Diabetic Vascular Calcification Via mA-Binding Protein HNRNPC.
Yang B, Mao X, Ren L … +6 more , Li L, Shao C, Wang X, Shi X, Xu S, Wang Z
Free Radic Biol Med · 2026 May · PMID 42191041 · Publisher ↗
BACKGROUND: Diabetes is one of the most common and fastest-growing diseases worldwide, and diabetic atherosclerotic calcification is a frequent and fatal complication, the underlying mechanisms of which remain unclear. I...
BACKGROUND: Diabetes is one of the most common and fastest-growing diseases worldwide, and diabetic atherosclerotic calcification is a frequent and fatal complication, the underlying mechanisms of which remain unclear. In this study, we investigated the mechanism by which HNRNPC regulates diabetic vascular calcification. METHODS: We retrieved datasets GSE211722, GSE84012, and GSE74755 from the GEO database and performed probe-to-gene name conversion. Based on expression profile data and aortic transcriptomic data from diabetic and non-diabetic mice, RNA m6A methylation-related regulatory genes were screened, and violin plots and heatmaps were generated accordingly. Differential genes identified from the expression profiles and experimental groups were subjected to intersection analysis to ultimately identify the target gene. We also enrolled coronary heart disease patients meeting predefined inclusion criteria to analyze the correlation between coronary artery calcium scores and serum HNRNPC levels. Subsequently, through transcription factor prediction and validation using single-cell transcriptomic data from the anterior tibial arteries of diabetic amputation patients, transcription factors of HNRNPC were identified. The role of HNRNPC in diabetic atherosclerotic calcification was further investigated by establishing an in vitro model of smooth muscle cells under high-glucose conditions and an in vivo model of diabetic atherosclerotic calcification in ApoE mice. RESULTS: Analysis of GEO datasets and diabetic mouse transcriptomic data identified HNRNPC as the only overlapping differentially expressed m6A methylation regulatory gene from both sources. Clinical investigations revealed that serum HNRNPC levels and coronary artery calcium scores were elevated in diabetic patients and exhibited a positive correlation. In vitro and in vivo experiments demonstrated that inhibiting HNRNPC reduced the expression of the osteogenic marker RUNX2 and decreased calcium deposition, whereas HNRNPC overexpression promoted calcification. By integrating bioinformatics analysis with cellular (MOVAS) and animal (ApoE mice) models, the transcription factor YY1 was revealed to play a pivotal role in vascular calcification. During calcification, YY1 expression was upregulated, and it directly bound to and activated the HNRNPC promoter, thereby enhancing HNRNPC transcription. Silencing YY1 significantly suppressed calcium deposition and osteogenic marker expression, whereas overexpressing HNRNPC reversed this effect, confirming that YY1 drives smooth muscle cell calcification by regulating HNRNPC expression. CONCLUSION: We demonstrate a previously unrecognized role of HNRNPC as a key driver of diabetic atherosclerotic calcification. Specifically, the transcription factor YY1 promotes calcification by mediating HNRNPC's function.
IL-6/STAT3 signaling drives mitochondrial oxidative phosphorylation dysfunction and AP-1 activation in fibroblasts during sepsis-induced lung injury.
Chen X, Jin X, Bao H … +9 more , Ma X, Guo Y, Yu Y, Gu H, Yu X, Xiang J, Sun J, Zhong Z, Shan Y
Free Radic Biol Med · 2026 May · PMID 42191040 · Publisher ↗
Sepsis-induced acute lung injury (ALI) and early fibrotic remodeling remain major clinical challenges with limited effective treatments. In this study, we systematically investigated the role of fibroblasts in sepsis-ass...
Sepsis-induced acute lung injury (ALI) and early fibrotic remodeling remain major clinical challenges with limited effective treatments. In this study, we systematically investigated the role of fibroblasts in sepsis-associated lung injury and fibrosis using single-cell RNA sequencing combined with functional validation. We found that fibroblast states shifted from a resting state toward pro-inflammatory and pro-fibrotic phenotypes during sepsis, including Glycoprotein-producing Fibroblasts, Stress-activated Fibroblasts, and Inflammatory Fibroblasts, accompanied by increased IL-6 signaling activity. Mechanistically, IL-6/Signal Transducer and Activator of Transcription 3 (STAT3) signaling was associated with impaired mitochondrial oxidative phosphorylation (OXPHOS) in fibroblasts, increased mitochondrial ROS production, and increased activation of the AP-1 transcription factor family, which was linked to enhanced profibrotic protein expression. Pharmacological intervention with clinically relevant glucocorticoids, dexamethasone and methylprednisolone, attenuated lung injury and fibrosis in experimental sepsis-associated lung injury and was associated with suppression of the IL-6/STAT3/OXPHOS/AP-1 axis. Collectively, these findings highlight IL-6/STAT3-mediated mitochondrial metabolic remodeling in fibroblasts as a potential therapeutic target for sepsis-induced lung injury and fibrosis.
Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.
Khodadadi E, Lu B
Free Radic Biol Med · 2026 May · PMID 42191039 · Full text
Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In a...
Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In addition to driving ATP synthesis through oxidative phosphorylation (OxPhos), MCI is a dynamic redox regulator that couples bidirectional catalysis with redox signaling. MCI conducts electron transfer in both the forward and reverse directions. While forward electron transport (FET) is essential for OxPhos and ATP synthesis, reverse electron transport (RET), driven by high membrane potential and ubiquinol pool, transfers electrons from ubiquinol to NAD and produces excessive ROS. MCI-derived ROS and NAD/NADH changes act as physiologically regulated signals mediating hypoxia sensing, immune activation, stem-cell metabolism, but they can also contribute to pathology when dysregulated as in ischemia-reperfusion, cancer, neurodegeneration, and aging. Recent cryo-EM structures, time-resolved studies, and multiscale molecular dynamics (MD) simulations have provided near-atomic views of MCI architecture and operational mechanics. Here we review these developments from a redox-centered perspective. By positioning MCI as a dynamic redox regulator within a spatially organized mitochondrial network, we aim to provide a unifying framework for understanding how directional electron transfer, proton translocation, and redox signaling are intertwined in mitochondrial biology.
Histone lactylation exacerbates neuronal ferroptosis after traumatic brain injury: The effect of the upregulation of TNFAIP3 by mediating mitochondrial damage through the deubiquitination of ENO1.
Zhou L, Xu Z, Hou X … +5 more , Ren H, Ni M, Gao L, Chen S, Li L
Free Radic Biol Med · 2026 May · PMID 42178000 · Publisher ↗
Alleviating various forms of programmed neuronal death resulting from mechanical injury has long driven the development of neurotherapeutic strategies for traumatic brain injury (TBI). This study aimed to elucidate the p...
Alleviating various forms of programmed neuronal death resulting from mechanical injury has long driven the development of neurotherapeutic strategies for traumatic brain injury (TBI). This study aimed to elucidate the potential role of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) in neuronal ferroptosis and to clarify the specific mechanisms through which it influences the prognosis of TBI. We observed differential expression of TNFAIP3 protein between TBI and sham-operated mice. Quantitative polymerase chain reaction (qPCR) and Western blot analyses revealed a significant upregulation of TNFAIP3 in neurons following brain injury. TNFAIP3 promoted stretch-induced neuronal ferroptosis and contributed to impaired motor and learning performance in mice after TBI. Mechanistically, TNFAIP3 stabilized Enolase 1 (ENO1) protein levels by mediating its deubiquitination. TNFAIP3-induced mitochondrial damage increased reactive oxygen species (ROS) production, ultimately exacerbating neuronal ferroptosis. Upregulation of TNFAIP3 in neurons was associated with enhanced histone lactylation following TBI. Lactic acid treatment further promoted neuronal ferroptosis by elevating TNFAIP3 expression. Collectively, our findings indicate that TNFAIP3 may serve as a potential therapeutic target for improving outcomes in patients with traumatic brain injury.
Multi-Omics Profiling of oxylipins and gene expression in pediatric sarcomas identifies metastatic signatures and prognostic models.
Chistyakov DV, Nikolskaya AI, Gorbatenko VO … +9 more , Goriainov SV, Prishchep PL, Kuzmin YB, Alferov AA, Kuznetsov IN, Varfolomeeva SR, Stilidi IS, Kushlinskii NE, Sergeeva MG
Free Radic Biol Med · 2026 May · PMID 42177999 · Publisher ↗
INTRODUCTION: Pediatric bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive malignancies with poor prognosis in the metastatic stage. Oxylipins, bioactive lipid mediators derived from polyun...
INTRODUCTION: Pediatric bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive malignancies with poor prognosis in the metastatic stage. Oxylipins, bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs), play a crucial role in inflammation, immunity, and cancer progression; however, their systemic profiles in pediatric sarcomas remain unexplored. METHODS: We performed UPLC-MS/MS-based metabolomic profiling of plasma oxylipins and PUFAs in 52 pediatric sarcoma patients (29 OS, 23 ES) and 20 healthy controls. Transcriptomic data from public datasets (GSE99671, TARGET-OS) were integrated to identify oxylipin-related dysregulated genes in osteosarcoma and to construct a prognostic model. RESULTS: Sarcoma patients exhibited distinct oxylipin profiles, with significant elevations in linoleic acid metabolites (9-HODE, 9-HpODE, 13-KODE), particularly in stage IV metastatic disease. Transcriptomic analysis revealed dysregulation of oxylipin metabolism genes, including PLA2G4B, CYP2C8, CYP4A22, CYP2S1, and cannabinoid metabolism genes FAAH and CNR1. Based on the analysis of 202 oxylipin metabolism-related genes, a 21-gene prognostic signature was derived, which effectively stratified osteosarcoma patients into high- and low-risk groups with significant survival differences. The model demonstrated high prognostic accuracy (AUC values of 0.910, 0.900, and 0.919 for 1-, 3-, and 5-year overall survival, respectively) and was validated in an independent cohort (GSE21257). CONCLUSIONS: This first comprehensive oxylipin metabolomics study in pediatric bone sarcomas identifies plasma lipid mediators as potential biomarkers for metastasis and prognosis. The integration of metabolomic and transcriptomic data highlights oxylipin pathway dysregulation as a key feature of sarcoma biology, offering new opportunities for risk stratification and targeted therapy.
4-N-furfurylcytosine, a novel cytosine-derived modulator of mitochondrial and redox homeostasis to counteract aging: Insights from cellular and mouse models.
Fedoruk-Wyszomirska A, Pawelczak P, Orlicka-Płocka M … +7 more , Gurda-Woźna D, Giel-Pietraszuk M, Przybył Ł, Framski G, Pasternak K, Chmurzynska A, Wyszko E
Free Radic Biol Med · 2026 May · PMID 42176909 · Publisher ↗
Mitochondrial dysfunction and redox imbalance are key features of aging that drive cellular senescence, metabolic decline, and tissue degeneration. 4-N-furfurylcytosine (FC), a cytosine derivative with redox-modulating p...
Mitochondrial dysfunction and redox imbalance are key features of aging that drive cellular senescence, metabolic decline, and tissue degeneration. 4-N-furfurylcytosine (FC), a cytosine derivative with redox-modulating properties, has been proposed to counteract age-associated oxidative damage; however, its effects in mammalian aging remain unexplored. The anti-aging potential of FC was investigated using a translational approach integrating in vitro and in vivo models. Human fibroblasts (MRC-5) and keratinocytes (HaCaT) subjected to physiological and stress-induced senescence were used to assess mitochondrial function, redox balance, and proteostasis, while aged C57BL/6J mice, long-term supplemented with FC were evaluated for systemic metabolic, molecular, and behavioral outcomes. FC enhanced cell survival and mitigated key hallmarks of senescence, including β-galactosidase activity and p16 expression. Moreover, FC reduced intracellular reactive oxygen species and oxidative damage, as evidenced by decreased levels of 8-oxodG, protein carbonyls, and lipid peroxidation. FC improved mitochondrial membrane polarization and increased ATP levels while reducing oxygen consumption, indicating an altered bioenergetic state. Proteomic profiling revealed enrichment of pathways related to mitochondrial maintenance, antioxidant defense, and proteostasis, consistent with enhanced metabolic adaptability. In aged mice, FC supplementation preserved lean body mass, improved coordination and endurance, stabilized lipid and glucose metabolism, maintained telomere integrity, increased mtDNA:nDNA ratio, and reduced systemic oxidative stress markers, indicating delayed molecular aging and preserved mitochondrial function without overt adverse effects detected in the measured readouts. 4-N-furfurylcytosine modulates redox- and mitochondria-associated aging phenotypes in cellular and mouse models, with effects consistent with remodeling of mitochondrial homeostasis and improved resilience to oxidative stress. These findings support FC as a promising candidate for further investigation as a modulator of aging-related processes.
CHD4 is a copper sensor linking chromatin remodeling to cuproptosis.
Wang Y, Chi R, Zhang C … +9 more , Liu Z, Tian X, Wang A, Sun Q, Miao Y, Xia J, Shi Y, Wang J, Zhang X
Free Radic Biol Med · 2026 May · PMID 42176908 · Publisher ↗
Cuproptosis is a copper-dependent regulated cell death pathway, but its connection to chromatin regulation is poorly understood. Here, we demonstrate that cuproptosis-sensitive tumor cells exhibit an "epigenetically prim...
Cuproptosis is a copper-dependent regulated cell death pathway, but its connection to chromatin regulation is poorly understood. Here, we demonstrate that cuproptosis-sensitive tumor cells exhibit an "epigenetically primed" state with elevated chromatin accessibility and active histone marks. Multi-omics analyses reveal extensive chromatin reprogramming, including topologically associating domain (TAD) fusion and global reduction of enhancer-associated loops. We identify the chromatin remodeler CHD4, a core subunit of the NuRD complex, as a direct copper sensor. Copper ions bind to the CXXC domain of CHD4, triggering its ubiquitin-mediated degradation. As a negative regulator, CHD4 loss causes chromatin decompaction and de-represses the transcription factor HSF2, which directly transactivates the key cuproptosis executor FDX1. Genetic and pharmacological validations confirm the copper-CHD4-HSF2-FDX1 axis as a central regulator of cuproptosis susceptibility. In patient-derived models, high HSF2/FDX1 expression predicts enhanced response to cuproptosis inducers. Our work establishes an epigenetic mechanism linking copper sensing to cuproptosis and nominates the CHD4/HSF2/FDX1 axis as potential biomarkers and therapeutic targets for precision oncology.
Rab26 mitigates ferroptosis in airway epithelium induced by cigarette smoke through suppression of VDAC1 oligomerization-mediated cGAS-STING activation.
Tian X, Zhang W, You Z … +11 more , Mao Y, Huang Q, Zeng L, Hu W, Wei D, Qian H, Zhang M, Luo L, Zhang J, Wang G, He B
Free Radic Biol Med · 2026 May · PMID 42176907 · Publisher ↗
BACKGROUND: Cigarette smoke (CS)-induced epithelial ferroptosis is a pivotal driver of airway inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Although Rab26 is known to protect against inflam...
BACKGROUND: Cigarette smoke (CS)-induced epithelial ferroptosis is a pivotal driver of airway inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Although Rab26 is known to protect against inflammatory injury, the precise molecular mechanism linking Rab26 to mitochondrial integrity and ferroptotic cell death remains largely unexplored. This study aims to elucidate a novel regulatory axis involving Rab26, mitochondrial voltage-dependent anion channel 1 (VDAC1), and the cGAS-STING pathway in the pathogenesis of COPD. METHODS: A COPD mouse model was established using Rab26-deficient (Rab26) mice exposed to cigarette smoke, alongside wild-type mice treated with a pharmacological STING inhibitor to validate pathway involvement. Ferroptosis and inflammation were assessed in vitro and in vivo. Crucially, we employed co-immunoprecipitation (Co-IP), chemical cross-linking, and transmission electron microscopy (TEM) to investigate the molecular interaction between Rab26 and VDAC1, and to monitor VDAC1 oligomerization and mitochondrial DNA (mtDNA) release. RESULTS: We observed significantly downregulated Rab26 expression in lung tissues from COPD patients and CS-exposed mice. In vivo, Rab26 deficiency markedly exacerbated airway inflammation, emphysema, and epithelial ferroptosis. Mechanistically, we identified a novel interaction wherein Rab26 physically binds to VDAC1. Under CS exposure, loss of Rab26 promotes VDAC1 oligomerization, leading to mitochondrial membrane permeabilization and the leakage of mtDNA into the cytosol. This cytosolic mtDNA subsequently triggers the aberrant hyperactivation of the cGAS-STING pathway, which represses the antioxidant SLC7A11/GPX4 axis and drives lethal ferroptosis. Conversely, restoring Rab26 or blocking STING signaling effectively inhibited VDAC1-mediated mtDNA release and alleviated ferroptotic injury. CONCLUSIONS: This study provides that Rab26 acts as a guardian of mitochondrial integrity by preventing VDAC1 oligomerization. We define a previously unrecognized Rab26-VDAC1-cGAS-STING signaling axis that regulates airway epithelial ferroptosis. Targeting this axis offers a compelling therapeutic strategy to arrest inflammation and disease progression in COPD.
Unveiling C1QBP: A New Guardian of Dopaminergic Neuron in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
Li J, Wang Y, Liu M … +9 more , Yu Z, Wang Y, Wang P, Guo C, Wang M, Shi R, Peng Y, Tan J, Lin Y
Free Radic Biol Med · 2026 May · PMID 42176906 · Publisher ↗
Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding prote...
Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding protein (C1QBP) plays a crucial role in regulating mitophagy and maintaining mitochondrial homeostasis. This study aims to investigate the role of C1QBP in the pathogenesis of PD by employing bidirectional modulation of C1QBP expression in the PD models. Our results showed reduced C1QBP expression in PD models. C1QBP deficiency aggravated motor dysfunction and dopaminergic neuron degeneration induced by MPTP, while its overexpression exerts protective effects. Mechanistically, C1QBP ameliorates MPP-induced mitochondrial dysfunction, thereby attenuating neuronal loss. Furthermore, C1QBP promotes mitophagy to maintain mitochondrial homeostasis in PD models. However, these neuroprotective effects of C1QBP were abolished upon UNC-51-Like Kinase 1 (ULK1) knockdown. Collectively, our study has identified C1QBP as a novel guardian for dopaminergic neurons in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
NRF2 coordinates ferroptosis and disulfidptosis in dermal papilla cells via redox metabolic reprogramming in androgenetic alopecia.
Mao X, Zhou W, An W … +4 more , Zhang J, Chen H, Sun M, Zhao H
Free Radic Biol Med · 2026 May · PMID 42173176 · Publisher ↗
Dysfunction of dermal papilla cells (DPCs) is a central feature of androgenetic alopecia (AGA), in which oxidative imbalance plays a critical role. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator...
Dysfunction of dermal papilla cells (DPCs) is a central feature of androgenetic alopecia (AGA), in which oxidative imbalance plays a critical role. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular redox homeostasis; however, its role in AGA remains unclear. Here, using primary DPCs, hair follicle organoids, and dihydrotestosterone (DHT)-induced mouse models, we found that NRF2 was markedly downregulated under AGA-associated conditions. Mechanistically, our data suggest that reduced NRF2 activity is associated with two distinct regulated cell death-related processes in DPCs: ferroptosis and disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF), together with molecular and metabolic analyses, indicated that impaired NRF2 signaling was linked to suppression of the SLC7A11-GSH-GPX4 axis, increased lipid peroxidation, and ferroptosis-related injury. In parallel, reduced NRF2 activity was associated with impaired pentose phosphate pathway (PPP) activity, NADPH depletion, disulfide stress, cytoskeletal disruption, and features consistent with disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF) effectively attenuates both ferroptosis and disulfidptosis, restoring hair follicle structure and promoting hair growth in AGA models. Collectively, our findings identify NRF2 as a central regulator linking redox metabolism to ferroptosis and disulfidptosis in DPCs, and highlight NRF2 activation as a potential therapeutic strategy for AGA.
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