Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
SKQ1 promotes tumor cell apoptosis by directly interacting with NDUFV2 and inducing superoxide production.
Tong X, Gao M, Qu L … +8 more , Jia L, Wang Z, Chen Y, Zhang M, Lu K, Han J, Hu Y, Gong G
Free Radic Biol Med · 2026 Aug · PMID 42119952 · Publisher ↗
SKQ1, a mitochondria-targeted antioxidant composed of triphenylphosphonium (TPP) and plastoquinone, has been reported to exhibit antitumor potential; however, its underlying mechanism of action and specific molecular tar...
SKQ1, a mitochondria-targeted antioxidant composed of triphenylphosphonium (TPP) and plastoquinone, has been reported to exhibit antitumor potential; however, its underlying mechanism of action and specific molecular targets remain largely unclear. Here, we investigated the antitumor efficacy of SKQ1 in vitro using human hepatocellular carcinoma cells (MHCC97-H) and murine colorectal cancer cells (MC38), and in vivo using a human-derived hepatocellular carcinoma xenograft model and a murine syngeneic colorectal cancer model. We found that SKQ1 induced apoptosis and inhibited the proliferation and migration of both MHCC97-H and MC38 in vitro; correspondingly, it also suppressed tumor development in a human-derived hepatocellular carcinoma xenograft model and a murine syngeneic colorectal cancer model established with these cells in vivo. It increased intracellular ROS levels. Mitochondria-targeted antioxidant Mito-TEMPO could rescue the pro-apoptotic effect of SKO1. Furthermore, NDUFV2 was identified as the direct target of SKQ1. SKQ1 binding to NDUFV2 induced the dysfunction of mitochondrial complex I, leading to a burst of ROS. NDUFV2 knockout eliminated the effect of SKQ1. Our findings demonstrated that SKQ1 exerts its antitumor effects by directly targeting NDUFV2, thereby inducing mitochondrial dysfunction and ROS-mediated apoptosis, which provides a mechanistic basis for developing SKQ1 as a potential anticancer therapeutic agent.
Salvianolic acid B ameliorates metabolic dysfunction-associated steatohepatitis in mice by inhibiting hepatocyte ferroptosis via regulation of the SIRT1/p53 axis.
Zhou X, Lv J, Liu W … +5 more , Mu Y, Chen G, Chen J, Liu P, Fu Y
Free Radic Biol Med · 2026 Aug · PMID 42119951 · Publisher ↗
BACKGROUND: MASH has become the most prevalent chronic liver disease worldwide. Hepatocyte ferroptosis is a key driver in the progression of MASH. Salvianolic acid B (Sal B), a natural antioxidant active ingredient, has...
BACKGROUND: MASH has become the most prevalent chronic liver disease worldwide. Hepatocyte ferroptosis is a key driver in the progression of MASH. Salvianolic acid B (Sal B), a natural antioxidant active ingredient, has an anti-MASH effect. However, the underlying mechanism by which Sal B inhibits hepatocyte ferroptosis and improves MASH remains unclear. METHODS: An in vivo MASH model was established by feeding C57BL/6J mice a HFHC diet for 30 weeks. In the 24th week, mice were treated with Sal B, obeticholic acid (OCA) or SRT1720. In vitro, over-expression and knockdown of SIRT1 in hepatocytes were constructed with lentivirus, subsequently, a hepatocyte lipid deposition model induced by palmitic acid/oleic acid (PO) or a hepatocyte ferroptosis model induced by erastin were used to investigate the efficacy and mechanism of Sal B. Furthermore, the interaction and binding kinetics of Sal B and SIRT1 were determined by molecular docking simulation, DARTS, CETSA and SPR assays. RESULTS: Sal B attenuated hepatic inflammation, lipid deposition and fibrosis in MASH mice. In situ transmission electron microscopy revealed characteristic morphological features of hepatocyte ferroptosis in the livers of MASH mice, which were alleviated by Sal B treatment. Mechanistically, Sal B up-regulated hepatic SIRT1 protein and inhibited p53 acetylation. In vitro, Sal B alleviated PO- or erastin-induced lipid deposition and ferroptosis in hepatocytes, along with up-regulating SIRT1 and inhibiting p53 acetylation. Similar protective effects were observed upon SIRT1 overexpression. Strikingly, SIRT1 knockdown reduced the inhibitory effect of Sal B on hepatocyte ferroptosis. SPR analysis confirmed moderate-affinity binding of Sal B to recombinant human SIRT1 protein, while DARTS and CETSA assays indicated that Sal B enhances SIRT1 enzymatic and thermal stability. CONCLUSION: Sal B ameliorates MASH in mice via directly regulating SIRT1/p53 signaling to suppress hepatocyte ferroptosis. Targeting hepatocyte ferroptosis through SIRT1 activation is a promising therapeutic strategy for MASH.
Carbon ions collapse the hypoxic lipid shield to decouple survival from redox vulnerability in NSCLC.
Ma N, Hu W, Deng Y … +2 more , Yuan L, Sun Y
Free Radic Biol Med · 2026 Aug · PMID 42119950 · Publisher ↗
Hypoxic non-small cell lung cancer (NSCLC) cells actively remodel lipid metabolism to construct a biochemical shield against lipotoxicity and oxidative stress. This adaptation drives a unidirectional phosphatidylcholine...
Hypoxic non-small cell lung cancer (NSCLC) cells actively remodel lipid metabolism to construct a biochemical shield against lipotoxicity and oxidative stress. This adaptation drives a unidirectional phosphatidylcholine to triacylglycerol conversion with a Z-score of 4.253. While clinically equivalent doses of conventional X-rays (6 Gy) leave the hypoxia-adapted lipidome intact and yield zero significantly altered lipid species, carbon ions radiation markedly rewire the lipidome, significantly displacing 79 lipid species. Combining carbon ions radiation with HIF-1α knockdown amplifies this displacement to 134 altered lipids. This profound structural remodeling is dominated by the exhaustion of phosphatidylcholine and sphingomyelin. Crucially, this metabolic shift occurs without additional acute clonogenic cell kill compared to carbon ions alone. This effectively decouples metabolic disruption from immediate reproductive death. Untargeted metabolomics confirms the concurrent collapse of mitochondrial electron transport and glutathione buffering. Carbon ions radiation effectively abrogate the hypoxic lipid shield. The resulting metabolically compromised survivor subpopulation, stripped of its antioxidant defenses, reveals a pronounced vulnerability to lipid peroxidation. Conventional survival-based relative biological effectiveness systematically underestimates this effect. This study provides defined redox-targeted mechanisms for deploying ferroptosis inducers as precision combination therapies in hypoxic solid tumors.
Targeting NLRP3 palmitoylation: Celastrol alleviates inflammasome activation induced by immunometabolism dysregulation in Kupffer cells.
Tao L, Fang Z, Gu W … +3 more , Li Y, Fan G, Yang X
Free Radic Biol Med · 2026 Aug · PMID 42119680 · Publisher ↗
Protein palmitoylation, the only reversible lipid-linked post-translational modification, acts as a critical regulatory mechanism for modulating protein function and subcellular localization. However, its specific roles...
Protein palmitoylation, the only reversible lipid-linked post-translational modification, acts as a critical regulatory mechanism for modulating protein function and subcellular localization. However, its specific roles and underlying mechanisms in the inflammatory response of liver macrophages (Kupffer cells) remain largely undefined. This study aimed to elucidate the precise mechanism by which palmitoylation regulates inflammation in Kupffer cells and to explore potential therapeutic interventions targeting this modification. Through metabolomic and membrane proteomic analyses, we demonstrated that LPS induces metabolic reprogramming, disrupts lipid homeostasis, and elicits palmitic acid accumulation in Kupffer cells. This lipid overload promotes NLRP3 palmitoylation at conserved cysteines Cys126 and Cys898, which in turn facilitates its translocation to the trans-Golgi network membrane and subsequent inflammasome activation. Targeting this palmitoylation switch thus represents a promising therapeutic strategy for inflammatory liver diseases. We further identified the natural compound celastrol as an effective inhibitor of NLRP3 palmitoylation. Mechanistically, this effect may be cooperatively mediated by the regulation of intracellular lipid metabolism and the covalent binding of celastrol to NLRP3. Our results uncover a novel mechanistic link between metabolic dysregulation and inflammasome activation in Kupffer cells mediated by palmitoylation. Importantly, we highlight celastrol as a promising therapeutic agent that targets immunometabolic crosstalk in the pathogenesis of inflammatory liver diseases.
Inhibition of HO-1 alleviates cardiac fibrosis by improving ferroptosis-mediated aberrant autophagy.
Kong C, Liu H, Jiang S … +11 more , He Y, Hu R, Wang H, Gong J, Zhu L, Yu T, Pang P, Ding D, Xuan H, Zhou Y, Shan H
Free Radic Biol Med · 2026 Aug · PMID 42114659 · Publisher ↗
Cardiac fibrosis is a major pathological feature of cardiovascular diseases and a key driver of ventricular remodeling and heart failure, yet effective therapeutic strategies remain limited due to incomplete mechanistic...
Cardiac fibrosis is a major pathological feature of cardiovascular diseases and a key driver of ventricular remodeling and heart failure, yet effective therapeutic strategies remain limited due to incomplete mechanistic understanding. Heme oxygenase-1 (HO-1), a key redox-regulating enzyme, has recently been implicated in cardiac injury. However, its role in cardiac fibrosis, particularly through the regulation of ferroptosis, remains poorly understood. This study systematically investigated the effects of HO-1-mediated ferroptosis on the progression of cardiac fibrosis. Myocardial infarction was induced by ligation of the left anterior descending coronary artery, and cardiac fibroblasts were stimulated with transforming growth factor-β1 (TGF-β1) to induce fibrosis. Ferroptosis was markedly activated, accompanied by increased ferrous iron (Fe) accumulation, enhanced reactive oxygen species (ROS) generation, and elevated levels of lipid peroxidation. Inhibition of ferroptosis significantly alleviated fibrotic responses and improved cardiac function. Mechanistically, ferroptosis suppression restored autophagic flux by correcting lysosomal abnormalities and normalizing LC3B and p62 accumulation. Furthermore, HO-1 was markedly upregulated in fibrotic conditions, promoting ferroptosis and myocardial fibrosis. Activation of HO-1 induced myocardial fibrosis by triggering ferroptosis-associated autophagic dysfunction, whereas HO-1 inhibition mitigated ferroptotic injury, restored autophagic homeostasis, and attenuated fibrosis. Blocking autophagy abolished the protective effects of HO-1 suppression, demonstrating that the antifibrotic role of HO-1-mediated ferroptosis is dependent on autophagic activity. These findings reveal a novel mechanism by which HO-1-mediated ferroptosis impairs autophagic homeostasis to drive cardiac fibrosis, highlighting HO-1 inhibition as a potential therapeutic strategy for attenuating cardiac fibrosis.
The IL-33/ST2 axis promotes sepsis-induced lung injury by modulating NETs formation via the ATF4/REDD1 signaling pathway.
Dai H, Zheng Y, Li C … +5 more , Yang B, Huang Q, Ran X, Ke S, Li Y
Free Radic Biol Med · 2026 Aug · PMID 42114658 · Publisher ↗
BACKGROUND: Neutrophil extracellular traps (NETs) can mediate sepsis-induced lung injury, but the upstream regulatory mechanisms remain unclear. IL-33 is involved in neutrophil activation and may serve as an upstream reg...
BACKGROUND: Neutrophil extracellular traps (NETs) can mediate sepsis-induced lung injury, but the upstream regulatory mechanisms remain unclear. IL-33 is involved in neutrophil activation and may serve as an upstream regulator of NET formation. Therefore, this study aims to elucidate the molecular mechanism by which the IL-33/ST2 axis regulates NET formation to mediate sepsis-induced lung injury. METHODS: A mouse model of sepsis-induced lung injury was established using the CLP method to assess lung damage and NETs formation. The destructive effect of NETs on the endothelial barrier was examined through DNase I intervention and HUVECs cell experiments. IL-33 or ST2 gene knockout mice were used to investigate the role of the IL-33/ST2 axis in sepsis-induced lung injury and its regulatory effect on NETs formation. Differentially expressed genes were identified via transcriptome sequencing of mouse neutrophils, and the downstream molecular mechanism of IL-33-induced NETs formation was explored by silencing or overexpressing REDD1 in dHL-60 cells. RESULTS: In septic mice, neutrophil infiltration and elevated levels of NETs were observed in lung tissue, accompanied by pulmonary edema and increased vascular permeability. These injuries were reversed by DNase I intervention. The IL-33/ST2 signaling axis was activated in septic mice, and knockout of either the IL-33 or ST2 gene alleviated lung injury, reduced endothelial barrier disruption, and inhibited NETs formation. In vitro experiments and transcriptome sequencing results demonstrated that IL-33 induces NETs formation in neutrophils through the ST2 receptor, and the ATF4/REDD1 signaling pathway is the key downstream mechanism by which IL-33 promotes NETs formation. CONCLUSION: This study demonstrates that IL-33/ST2 signaling leads to activation of the PERK/eIF2α/ATF4 pathway in neutrophils, upregulates REDD1 to induce NETosis triggered by oxidative stress, and thereby disrupts the pulmonary vascular endothelial barrier, exacerbating sepsis-induced lung injury.
Nano-selenium attenuates cadmium-induced ER-phagy through inhibition of TFEB nuclear translocation and FAM134B downregulation.
Liang YS, Du JY, Cai WN … +4 more , Guo K, Meng WJ, Li JL, Li XN
Free Radic Biol Med · 2026 Aug · PMID 42107477 · Publisher ↗
Cadmium (Cd) is a well-documented environmental pollutant associated with male reproductive disorders, necessitating the urgent development of effective therapeutic agents. Nano-selenium (Nano-Se) represents an advanced...
Cadmium (Cd) is a well-documented environmental pollutant associated with male reproductive disorders, necessitating the urgent development of effective therapeutic agents. Nano-selenium (Nano-Se) represents an advanced selenium supplement with robust antioxidant properties, which can mitigate various forms of heavy metal toxicity. However, the role of Nano-Se in alleviating Cd-induced testis damage remains unclear. Family with sequence similarity 134 member B (FAM134B) is the first identified Endoplasmic reticulophagy (ER-phagy) receptor, and the ER-phagy it mediates plays a crucial role in the reproductive system. In this study, Hy-line White roosters were randomly divided into four groups and subjected to a 90-day observation period. Serum samples and testicular tissue samples from roosters were collected for subsequent detection. Hematoxylin-eosin (H&E) staining, periodic acid-Schiff (PAS) staining, ELISA kit detection, Western blotting (WB), immunofluorescence (IF), cellular thermal shift assay (CETSA) and molecular docking techniques were employed to explore the effects of Cd on the reproductive system and the alleviating effect of Nano-Se. In vivo assays revealed that Nano-Se efficiently mitigated testicular atrophy and histological damage triggered by Cd exposure. Nano-Se reversed the Cd-mediated inhibition of steroidogenesis-related proteins, and elevated the expression of Leydig cell markers including 3β-HSD and INSL3, thereby ameliorating Cd-evoked Leydig cell dysfunction. Consistent with in vivo outcomes, in vitro tests using primary rooster Leydig cells demonstrated that Nano-Se notably restrained Cd-activated ER-phagy and excessive lysosomal acidification. Mechanistically, such protective effects were achieved by blocking TFEB nuclear translocation and preventing the downregulation of FAM134B. This present study provides a foundation for preclinical research for its usefulness as a potential therapeutic for reproductive toxicity induced by environmental heavy metal pollutants.
Fyn promotes NLRP3 inflammasome activation in microglia and exacerbates early brain injury following subarachnoid hemorrhage.
Ping K, Zhao P, Zhou J … +6 more , Xin Y, Hu B, Zhang B, Xu D, Li A, Sun Y
Free Radic Biol Med · 2026 May · PMID 42107476 · Publisher ↗
BACKGROUND: Subarachnoid hemorrhage (SAH) is a lethal stroke subtype with high mortality. Microglia-driven neuroinflammation plays a pivotal role in early brain injury (EBI) after SAH. Xanthotoxol (Xol), a natural furano...
BACKGROUND: Subarachnoid hemorrhage (SAH) is a lethal stroke subtype with high mortality. Microglia-driven neuroinflammation plays a pivotal role in early brain injury (EBI) after SAH. Xanthotoxol (Xol), a natural furanocoumarin, exhibits anti-inflammatory properties and neuroprotective potential, yet its role in SAH remains unclear. This study investigates whether Xol alleviates SAH-induced neuroinflammation and its underlying mechanisms. METHODS: SAH was induced in male SD rats and Balb/c mice via endovascular perforation. Three weeks prior to the SAH surgery, AAV2/9-CX3CR1-ZsGreen-miR30-Fyn virus was injected into the medial prefrontal cortex for in vivo mechanistic investigations. In vitro SAH models were established using oxyhemoglobin-stimulated microglia and microglia-neuron co-cultures. Finally, the efficacy of Xol was investigated both in vivo and in vitro following SAH. Assessments included neurological and cognitive function evaluation, brain water content measurement, detection of apoptosis, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, immunohistochemistry, and Nissl staining. RESULTS: Fyn was upregulated in microglia post-SAH and associated with neuroinflammatory and apoptotic pathways via proteomics. Its knockdown ameliorated neurological deficits, edema, neuronal injury, and NLRP3 activation. Mechanistically, Fyn promoted K48-linked ubiquitination and degradation of Sirt1 via E3 ligase C-cbl. Xol directly bound Fyn, inhibiting its kinase activity and NLRP3 activation, thereby mitigating brain injury. CONCLUSION: This study revealed Fyn recruits E3 ligase C-cbl to mediate Sirt1-K48 ubiquitination/degradation, activating NLRP3 inflammasome to drive SAH-induced neuroinflammation and brain injury. Xol inhibits Fyn activation, thereby attenuating inflammatory injury. The Fyn/Sirt1 axis represents a novel therapeutic target, and Xol offers a promising natural strategy for SAH treatment.
Exhaled 3-nitrotyrosine is associated with non-allergic asthma in adults from the EGEA study.
Sahraoui E, Masso V, Raymond P … +8 more , Achour D, Grare C, Siroux V, Orsi L, Lo Guidice JM, Matran R, Zerimech F, Nadif R
Free Radic Biol Med · 2026 Aug · PMID 42105794 · Publisher ↗
The role of exhaled 3-nitrotyrosine (3-NT) beyond the severe asthma phenotype remains largely unexplored. Associations of exhaled 3-NT with allergy and with various asthma characteristics were studied in 792 adults from...
The role of exhaled 3-nitrotyrosine (3-NT) beyond the severe asthma phenotype remains largely unexplored. Associations of exhaled 3-NT with allergy and with various asthma characteristics were studied in 792 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA, 40% current asthmatics, 56% allergic, 36% adult-onset asthma). Asthma characteristics were defined using questionnaires, and allergy by a positive skin prick test. 3-NT was analyzed as categorical, continuous and ratio (3-NT/tyrosine) variables. Cross-sectional analyses showed that high 3-NT levels were associated with an increased risk of current asthma (adjusted(a)OR [95%CI] = 1.61 [1.09-2.38], particularly in non-allergic asthma (aOR = 2.19 [1.09-4.41]), and no association was found with allergy. Results were consistent across all 3-NT expressions. Longitudinal analyses showed that high 3-NT levels were associated with persistent current asthma at 10-year follow-up. Our results advance understanding of the mechanisms underlying asthma phenotypic heterogeneity, thereby opening new perspectives in its management.
pH-regulated ''ON/OFF″ glucose oxidase nanoparticles for synergistic therapy and amplification of immunogenic cell death.
Wang Z, Bai H, Shen X … +6 more , Feng D, Zhang S, Lee RJ, Tang Y, Xie J, He X
Free Radic Biol Med · 2026 Aug · PMID 42105793 · Publisher ↗
Although the combination of glucose oxidase (GOx)-based starvation therapy and chemodynamic therapy (CDT) has shown great potential, the severe systemic toxicity caused by the non-specific activity of GOx in the blood ci...
Although the combination of glucose oxidase (GOx)-based starvation therapy and chemodynamic therapy (CDT) has shown great potential, the severe systemic toxicity caused by the non-specific activity of GOx in the blood circulation and the insufficient immunogenic cell death (ICD) effect induced by doxorubicin (DOX) jointly restrict its clinical transformation. In this paper, an intelligent nanoplatform (GTF-DOX) integrating pH-responsive enzyme activity switch, multi-mode synergistic therapy, and immune activation is reported. Through the acid-sensitive Schiff base bond formed between 2,3,4-trihydroxybenzaldehyde (TB) and GOx, the platform realizes the 'off' of GOx activity in the blood and the specific 'on' in the tumor microenvironment, eliminating the risk of hypoglycemia from the root. At the same time, Fe bridges GOx-TB and DOX to construct a compact integrated synergistic delivery system, and the cell uptake efficiency is significantly improved by DOX-mediated charge reversal and membrane penetration. Experiments have shown that GTF-DOX can cascade drive starvation therapy, high-efficiency CDT, and chemotherapy after being activated at the tumor site, resulting in a strong synergistic anti-tumor effect. The severe oxidative stress caused by this process and DOX synergistically enhances the ICD effect, successfully triggering calreticulin (CRT) exposure, high mobility group protein B1 (HMGB1), and ATP release, thereby promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration, and stimulating a strong anti-tumor immune response in the 4T1 tumor-bearing mouse model. In this study, the problems of safety and synergistic efficacy were solved simultaneously through ingenious chemical design, providing a new paradigm for the development of intelligent tumor combination therapy.
Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.
Carlini NA, Hanson BE, Ruple BA … +12 more , Craig JC, Fermoyle CC, McKenzie AI, Bisconti AV, Pelka EZ, Supiano MA, Tuday E, Richardson RS, Drummond MJ, Rajasekaran NS, Broxterman RM, Trinity JD
Free Radic Biol Med · 2026 May · PMID 42105792 · Publisher ↗
Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) s...
Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27±7 y) and 24 older adults (12M/12F, age 67±8 y) were randomized to receive either placebo or PB125 (200 mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8±1.5 to 3.8±1.3%, p<0.0001) and popliteal FMD (PB125: 1.5±1.5 to 2.3±1.4%, p=0.033) in older, but not younger adults (both, p>0.27). During bed rest, PB125 preserved brachial (3.8±1.3 to 3.6±1.4%, p=0.543) and popliteal FMD (2.3±1.4 to 2.7±1.4%, p=0.269), LVC (1.1±0.8 to 1.1±1.5 AUC, p=0.530) and circulating SOD concentrations (28.3±7.2 to 28.6±8.6 U/mL, p=0.888) in older adults compared to placebo (all, p<0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4±2.8 to 3.4±1.8%, p=0.302) in younger adults compared to placebo (p<0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.
The protective role of aldo-keto reductase family 1 member A1 in kidney allograft injury: beyond S-nitrosylation.
Tsai YL, Liou YM, Chen CM … +3 more , Wu CL, Hsu CY, Weng SC
Free Radic Biol Med · 2026 Aug · PMID 42105791 · Publisher ↗
Aldo-keto reductase family 1 member A1 (AKR1A1) is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme that catalyzes the reduction of aldehydes to alcohols. In this study, we investigated whether AKR1...
Aldo-keto reductase family 1 member A1 (AKR1A1) is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme that catalyzes the reduction of aldehydes to alcohols. In this study, we investigated whether AKR1A1 acts as a context-dependent stress-associated factor whose role may differ depending on the degree, duration, and cellular context of injury in kidney allografts and explored its underlying molecular mechanisms. In human kidney transplant specimens, AKR1A1 expression was upregulated in renal tubular epithelial cells (RTECs) exhibiting tubular injury and oxidative stress, particularly during rejection accompanied by acute tubular injury. Although AKR1A1 expression showed an inverse correlation with pyruvate kinase muscle isoenzyme 2 (PKM2), this association was statistically non-significant. Notably, higher AKR1A1 expression was associated with increased oxidative stress yet correlated with a reduced risk of serum creatinine doubling in this cohort. In vitro, hypoxia/reoxygenation (H/R) reduced cell viability and induced AKR1A1 expression alongside the pro-apoptotic marker C/EBP homology protein (CHOP). Pharmacological inhibition of S-nitrosoglutathione reductase using N6022 functionally attenuated AKR1A1 activity without a direct effect on CHOP expression. Genetic modulation further confirmed the role of AKR1A1 in apoptosis, as AKR1A1 knockdown increased CHOP expression, whereas AKR1A1 overexpression attenuated it. Reciprocal activation between AKR1A1 and the silent information regulator 1 (SIRT1)/peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway was observed both in vitro and in vivo. In addition, N6022 altered LC3B-associated autophagy markers, suggesting the activation of compensatory cytoprotective mechanisms under conditions of AKR1A1 deficiency. Together, these findings indicate that AKR1A1 serves as a marker of tubular stress and contributes to kidney allograft survival by modulating CHOP-mediated apoptosis and the SIRT1/PGC-1α axis. Inhibitory S-nitrosylation and activation of SIRT1/PGC-1α provide compensatory protection against oxidative stress and apoptosis. Targeting these pathways may represent a promising therapeutic strategy to improve kidney allograft outcomes.
FMO1 disrupts mitochondrial functional homeostasis through ROS-mediated mechanisms to drive chondrocyte senescence and hypertrophy.
Tang R, Guo D, Li S … +6 more , Wang S, Yin J, Yang J, Yang J, Fei J, Zhou Z
Free Radic Biol Med · 2026 Aug · PMID 42105790 · Publisher ↗
OBJECTIVE: The induced membrane technique is a clinical strategy for managing large bone defects, which relies on endochondral ossification. However, the metabolic mechanisms regulating this process remain largely unchar...
OBJECTIVE: The induced membrane technique is a clinical strategy for managing large bone defects, which relies on endochondral ossification. However, the metabolic mechanisms regulating this process remain largely uncharacterized. We utilized scRNA-seq to analyze chondro-osseous dynamics during membrane-induced osteogenesis, with a specific focus on the role of FMO1. METHODS: Following the scRNA-seq profiling of human induced membranes, FMO1 function was examined using in vivo and in vitro models of triiodothyronine (T3)-induced chondrocyte hypertrophy. Mechanistic investigations incorporated FMO1 genetic knockdown and overexpression, pharmacological inhibition (methimazole), targeted mitochondrial functional assays, and senolytic clearance (ABT-263). RESULTS: FMO1, an enzyme typically associated with xenobiotic metabolism, was upregulated during chondrocyte hypertrophy. Both T3 stimulation and direct FMO1 overexpression increased intracellular and mitochondrial reactive oxygen species. This localized oxidative stress altered mitochondrial homeostasis by shifting organelle dynamics toward fission, characterized by Drp1 upregulation and Mfn1/2 downregulation. This structural imbalance induced cellular senescence via the p16/p21 axis, resulting in abnormal matrix mineralization and increased expression of catabolic markers (COL10A1, MMP13). Genetic knockdown or pharmacological inhibition of FMO1, as well as the clearance of senescent cells, reduced these hypertrophic and senescent phenotypes. CONCLUSIONS: We describe an FMO1-ROS-mitochondria axis that links metabolic oxidative stress to chondrocyte senescence. While baseline FMO1 expression occurs during physiological bone repair, its sustained activation drives pathological calcification and cartilage degeneration. Targeting this axis presents a potential biological strategy for modulating the osteogenic microenvironment and managing cartilage disorders.
Plasma glycine decelerates biological aging via the redox-inflammatory axis: A large-scale study modulated by sex and dietary patterns.
Xu H, Pan S, Qi H … +6 more , Liu X, Geng G, Qi X, Wei W, Li Y, Wang X
Free Radic Biol Med · 2026 Aug · PMID 42105789 · Publisher ↗
BACKGROUND: Glycine serves as a critical substrate for glutathione synthesis and a critical modulator of redox homeostasis. However, whether plasma glycine is associated with biological aging, and the underlying interpla...
BACKGROUND: Glycine serves as a critical substrate for glutathione synthesis and a critical modulator of redox homeostasis. However, whether plasma glycine is associated with biological aging, and the underlying interplay between oxidative stress, inflammation, and dietary context remains unclear. METHODS: We analyzed the UK Biobank data to investigate the association between plasma glycine and biological aging, primarily assessed by the Klemera-Doubal Method (KDM) residuals. Restricted cubic splines were used to assess the nonlinear relationships. Mediation analysis assessed the roles of inflammatory and oxidative stress markers. Interactive analysis was applied to explore the relationship between comprehensive dietary patterns and glycine-related aging. RESULTS: Higher plasma glycine was negatively associated with KDM residuals (β: -0.729, 95%CI: -0.815, -0.643). Mediation analysis demonstrated that the inverse glycine-aging association was partially explained by reduced systemic inflammation and modulation of redox biomarkers (mediation proportions: 3.9% to 25.6%). Exploratory in silico Gene Ontology (GO) analysis provided supportive evidence implicating oxidative stress and inflammatory responses in these pathways. Notably, we identified a sex-specific diet interaction, the inverse association between glycine and KDM residuals was attenuated in males consuming a pro-inflammatory and pro-oxidative diet (β: -0.757, 95%CI: -1.294, -0.220) compared to the anti-inflammatory and anti-oxidative diet group (β: -0.939, 95%CI: -1.402, -0.476) (p for interaction = 0.014). No such interaction was observed in females. CONCLUSION: Plasma glycine negatively correlated with biological aging, partly through modulation of the redox-inflammatory axis. The male-specific vulnerability to pro-oxidative and pro-inflammatory diets highlights that glycine's efficacy is contingent upon a favorable nutritional context. These results support for precision interventions integrating glycine optimization with anti-inflammatory dietary patterns to extend healthy longevity.
Corrigendum to "Redox-dependent suppression of ATF3 impairs steroid sensitivity in asthma through MKP-1/p38 MAPK signaling" [Free Radic. Biol. Med. 243 (2026) 1-15].
Li J, Zhao L, Qiu Y … +5 more , Liao J, Tian X, Gao J, Zhang M, Bao A
Free Radic Biol Med · 2026 Aug · PMID 42103521 · Publisher ↗
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YOD1 Regulates Neuronal Mitochondrial Unfolded Protein Response Activation by Deubiquitinating DNAJA1 After Subarachnoid Hemorrhage.
Liu X, Gao B, Bai L … +7 more , Lu D, Song Z, Wang Z, Li D, Ma C, Li H, Wang Z
Free Radic Biol Med · 2026 May · PMID 42103167 · Publisher ↗
BACKGROUND: Mitochondrial dysfunction plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH) and represents a promising therapeutic target.The mitochondrial unfolded protein response (U...
BACKGROUND: Mitochondrial dysfunction plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH) and represents a promising therapeutic target.The mitochondrial unfolded protein response (UPR) maintains mitochondrial homeostasis and enables neurons to cope with oxidative stress. In this study, we explored UPR activation mediated by OTU-deubiquitinating enzyme 1 (YOD1) / DnaJ homolog subfamily A member 1 (DNAJA1) and its role in SAH. METHODS: We isolated UPR positive (UPR) and UPR negative (UPR) primary neurons by flow cytometry and validated their differential tolerance to oxidative stress following SAH. We then explored the underlying causes of differential levels of UPR activation. By combining molecular docking, co-immunoprecipitation, and protein stability assays, we established that YOD1 regulates the deubiquitination of DNAJA1. In addition, we assessed the neuroprotective role of YOD1 after SAH in vivo and in vitro models. RESULTS: UPR neurons exhibited reduced oxyhemoglobin (OxyHb)-induced apoptosis and mitochondrial damage compared with UPR neurons. DNAJA1 was upregulated and binding to HSP70 led to a strong activation of UPR. DNAJA1 stability was regulated by the ubiquitin-proteasome system, and YOD1 stabilized DNAJA1 via deubiquitination. Neuron-specific YOD1 overexpression preserved mitochondrial function, reduced neuronal apoptosis in vitro and in vivo, and improved neurological outcomes in SAH. CONCLUSION: YOD1 stabilizes DNAJA1 through deubiquitination, promoting UPR activation to mitigate mitochondrial dysfunction and neuronal death during EBI following SAH.
Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis.
Wang SF, Chou HY, Liu PH … +8 more , Su HH, Hung GY, Chou CY, Tseng LM, Shen YC, Yen JC, Huang SS, Lee HC
Free Radic Biol Med · 2026 Aug · PMID 42103166 · Publisher ↗
Doxorubicin is an effective chemotherapeutic agent; however, its use is limited by cardiotoxicity. Mitochondrial dysfunction is a central driver of doxorubicin-mediated cardiotoxicity. The role of the integrated stress r...
Doxorubicin is an effective chemotherapeutic agent; however, its use is limited by cardiotoxicity. Mitochondrial dysfunction is a central driver of doxorubicin-mediated cardiotoxicity. The role of the integrated stress response (ISR), a mitochondria-to-nucleus signaling pathway and crucial cellular defense mechanism in doxorubicin-induced cardiotoxicity, remains unclear. We investigated the pharmacological ISR activator salubrinal, a selective inhibitor of eukaryotic initiation factor 2α dephosphorylation with potential cardioprotective properties, to elucidate the molecular mechanisms underlying ISR-mediated cardioprotection in H9c2 cardiomyocytes, C57BL/6 mice, and HL-1 cell models. Doxorubicin disrupts ISR signaling, whereas salubrinal alleviates cardiotoxicity by activating transcription factor 4 (ATF4, a central ISR hub)-dependent pathways that suppress doxorubicin-induced apoptosis and preserve mitochondrial metabolism. The cystine/glutamate antiporter xCT, essential for glutathione (GSH) homeostasis, and growth differentiation factor 15 (GDF15), a mitochondrial stress-induced mitokine and potential biomarker of doxorubicin cardiotoxicity, are both regulated by ATF4. Mechanistically, we found that salubrinal contributes to cardioprotection against doxorubicin by enhancing the GSH-based antioxidant capacity via the ATF4-dependent GDF15-xCT axis. Further analysis of ATF4-associated GSH regulatory pathways revealed that enzymes involved in serine metabolism and glutathione peroxidase 4, a critical enzyme in GSH utilization that is upregulated by ATF4-mediated heat shock 70 kDa protein 5 and cystathionine gamma-lyase, contribute to the cardioprotective effects of salubrinal against doxorubicin-induced oxidative stress. Our findings highlight the ISR as a vital survival mechanism in cardiomyocytes exposed to doxorubicin. Regulating antioxidant defenses through enhanced GSH homeostasis and ISR activation, particularly via pharmacological agents such as salubrinal, may offer a promising therapeutic strategy for mitigating doxorubicin-induced cardiotoxicity.
Lysosomal function, resistance to oxidative stress and repair are compromised by expression of the Alexander disease GFAP R239C mutant.
Hernández-Gerez E, Goya-Iglesias N, Viedma-Poyatos Á … +2 more , Pajares MA, Pérez-Sala D
Free Radic Biol Med · 2026 Aug · PMID 42103165 · Publisher ↗
Intermediate filaments are critical regulators of cell responses and organizers of cellular structures. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that provides structural and functional s...
Intermediate filaments are critical regulators of cell responses and organizers of cellular structures. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that provides structural and functional support to astrocytes. GFAP is a key target of oxidative stress and its expression and assembly are altered in brain disease and injury. Moreover, GFAP mutations can provoke protein aggregation and proteostasis defects, astrocytic damage and ultimately neurodegeneration causing the leukodystrophy known as Alexander disease (AxD). We previously showed mitochondrial alterations and oxidative stress in astrocytes expressing GFAP AxD mutants. Here, we address the impact of GFAP AxD mutants on the lysosomal degradation pathway, using an astrocytoma cell model. Lysosomes in cells expressing GFAP R239C, a variant associated with severe AxD, displayed abnormal distribution, defective activity and impaired intraluminal acidification. Lysosomes are primary sites of oxidative damage. Expression of GFAP R239C increased their susceptibility to oxidative stress, provoking a greater loss of lysosomal "mass" and compromised membrane integrity, revealed by increased intraluminal galectin recruitment, compared to cells expressing GFAP wt. Notably, lysosomes in GFAP R239C expressing cells were also more vulnerable to chemically-induced rupture. Interestingly, whereas lysosomes of cells expressing GFAP wt rapidly recovered after removal of the damaging agent, recovery of acidic vesicles was severely impaired in cells expressing GFAP R239C, suggesting a defect in lysosomal repair. Together, our results show that expression of the GFAP R239C AxD mutant is sufficient to deeply perturb lysosomal distribution, function and repair. These alterations could contribute to proteostasis defects and cellular toxicity in AxD.
An integrated study of gut microbiota and serum metabolites in T2DM-ED rats after fecal microbiota transplantation.
Cheng C, Zheng L, Bao X … +3 more , Wei L, Jiang H, Jiang T
Free Radic Biol Med · 2026 Aug · PMID 42103164 · Publisher ↗
Erectile dysfunction (ED) is a highly prevalent and refractory complication of type 2 diabetes mellitus (T2DM), with penile cavernosal dysfunction, inflammation, apoptosis, and fibrosis as core pathological features. Her...
Erectile dysfunction (ED) is a highly prevalent and refractory complication of type 2 diabetes mellitus (T2DM), with penile cavernosal dysfunction, inflammation, apoptosis, and fibrosis as core pathological features. Here we identify gut microbiota dysbiosis and its downstream metabolite arachidonic acid (AA) as critical mediators of T2DM-associated erectile dysfunction (T2DM-ED) through a systemic gut-penis axis. Gut dysbiosis is sufficient to induce an ED phenotype, as demonstrated by fecal microbiota transplantation (FMT) from T2DM-ED rats into pseudo-germ-free recipients, which successfully transferred the erectile impairment with significantly decreased ICP/MAP ratios. Recipient rats showed impaired colonic barrier integrity, mucosal damage, goblet cell depletion, and downregulated tight junction proteins (Occludin, Claudin-4). Multi-omics integration of 16S rRNA sequencing and serum metabolomics identified AA as a key elevated metabolite that drives inflammatory signaling via the HIF-1α and NF-κB pathways. In penile corpus cavernosum tissue, ED-FMT rats displayed smooth muscle loss, fibrosis, increased apoptosis, and hyperactivation of the TLR4-MyD88-NF-κB-HIF-1α axis. In primary corpus cavernosum smooth muscle cells (CCSMCs), AA stimulation recapitulated pathological activation, including a pro-apoptotic shift in the Bax/Bcl-2 ratio, elevated Cleaved Caspase-3, reduced α-SMA, increased COX-2, stabilized HIF-1α, and excessive PGE production; these effects were abolished by pharmacological inhibition of NF-κB. Mechanistically, gut dysbiosis-induced systemic AA accumulation triggers inflammatory damage, apoptosis, and functional impairment in penile smooth muscle via the TLR4-MyD88-NF-κB/HIF-1α cascade. These findings define a gut-AA-NF-κB-penis axis that drives T2DM-ED pathogenesis, highlighting AA and its downstream signaling as promising therapeutic targets for diabetic erectile dysfunction.
Ski promotes KLF4 expression to drive astrocyte senescence through the JAK2/STAT3 pathway after spinal cord injury in rats.
Shi Y, Song K, Zhou W … +7 more , Dong Y, Song W, Ran R, Zhao G, Zhou K, Nan W, Zhang H
Free Radic Biol Med · 2026 Aug · PMID 42103163 · Publisher ↗
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