Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
NDP52-mediated autophagic degradation of CAPZA1 ameliorates intervertebral disc degeneration by suppressing cellular senescence.
Yao GL, Xie XS, Wang SJ … +6 more , Jiang HX, Xiong X, Du LX, Liu JM, Song HH, Liu ZL
Free Radic Biol Med · 2026 Aug · PMID 42061478 · Publisher ↗
Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, characterized by the progressive senescence of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) catabolism. Although bulk autophagy...
Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, characterized by the progressive senescence of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) catabolism. Although bulk autophagy has been implicated in the pathogenesis of IVDD, the specific contribution of selective autophagy to NPC fate remains largely unexplored. Here, we identify NDP52, a selective autophagy receptor, as a critical regulator of NPC homeostasis. NDP52 expression was significantly downregulated in degenerative NP tissues from humans, aged mice and needle puncture-induced IVDD models. NDP52 deficiency promoted NPC senescence, characterized by cell cycle arrest, senescence-associated secretory phenotype (SASP) factor secretion and reactive oxygen species (ROS) accumulation, ultimately leading to impaired ECM homeostasis, whereas NDP52 overexpression exerted opposite effects. In vivo, NDP52 knockout mice exhibited more severe disc degeneration and heightened pain sensitivity than wild-type controls. Deletion of the ZF2 domain abolished the protective effects of NDP52 in NPCs, indicating that its selective autophagy function is required for maintaining NPC homeostasis. Integrated proteomic and IP-MS analyses identified CAPZA1 as a candidate substrate of NDP52. Subsequent biochemical analyses demonstrated that NDP52 promotes the autophagic degradation of CAPZA1, an F-actin capping protein, through its ZF2 domain. Loss of NDP52 resulted in CAPZA1 accumulation, which was accompanied by aberrant ROS accumulation and activation of p53/Rb-dependent cell cycle arrest and NF-κB-mediated SASP signaling. CAPZA1 knockdown rescued the senescent and degenerative phenotypes caused by NDP52 deficiency. These findings identify the NDP52-CAPZA1 selective autophagy axis as a key protective mechanism against IVDD and highlight potential therapeutic targets for this prevalent degenerative disorder.
Targeting STIM1 attenuates LPS-induced cardiac dysfunction by reshaping calcium homeostasis and mitochondrial function.
Wu QR, Luo LB, Yang H … +7 more , Rao F, Zhang MZ, He JT, Cai YJ, Wang Q, Chen CB, Deng CY
Free Radic Biol Med · 2026 Aug · PMID 42044751 · Publisher ↗
Dysregulated calcium homeostasis and mitochondrial impairment are critical factors in the pathogenesis of sepsis-induced cardiomyopathy (SICM). STIM1 is crucial for maintaining calcium homeostasis. However, whether impro...
Dysregulated calcium homeostasis and mitochondrial impairment are critical factors in the pathogenesis of sepsis-induced cardiomyopathy (SICM). STIM1 is crucial for maintaining calcium homeostasis. However, whether improving STIM1-mediated calcium handling can alleviate SICM remains unknown. This study aims to clarify the mechanism and the role of STIM1 in SICM. In this study, we first established a rat model of sepsis induced by LPS and clarified that the upregulation of STIM1 protein is associated with SICM. Myocardial-specific knockdown of STIM1 significantly improved cardiac function in septic rats. Moreover, using the calcium influx inhibitor BTP2, we elucidated that BTP2 could alleviate SICM by improving calcium handling and mitochondrial function. Subsequently, we treated cardiomyocytes with LPS to explore the mechanism by which STIM1 promotes SICM. The results demonstrated that STIM1 amplifies store-operated calcium entry, triggering concomitant cytosolic and mitochondrial calcium overload. This induces Drp1-dependent mitochondrial fragmentation and dysfunction, resulting in elevated ROS production and subsequent activation of the NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes, ultimately leading to SICM. In conclusion, this study indicate that STIM1 promotes calcium overload, thereby facilitating mitochondrial dysfunction and ultimately resulting in pyroptosis. Targeting STIM1 may thus represent a promising therapeutic strategy for SICM.
Early life nutrition and redox dysregulation: Implications for lifelong metabolic health.
Ersoy U, Goljanek-Whysall K, Vasilaki A
Free Radic Biol Med · 2026 Aug · PMID 42036093 · Publisher ↗
Early-life growth patterns are increasingly recognised as critical determinants of long-term health trajectories. A substantial body of evidence links suboptimal growth during early development with an elevated risk of c...
Early-life growth patterns are increasingly recognised as critical determinants of long-term health trajectories. A substantial body of evidence links suboptimal growth during early development with an elevated risk of chronic, age-related disorders in adulthood. In particular, maternal undernutrition leading to foetal growth restriction, especially when followed by rapid postnatal catch-up growth, markedly increases susceptibility to cardiometabolic and other degenerative diseases later in life. Conversely, maternal overnutrition and associated metabolic disturbances also exert lasting effects on offspring physiology, predisposing individuals to conditions such as cardiovascular disease, type-2 diabetes, and metabolic syndrome. Emerging mechanistic insights highlight redox imbalance as central mediator of maternal nutrition-induced developmental programming. Perturbations in oxidative homeostasis during critical windows of development can induce persistent alterations in cellular energetics, metabolic regulation, and tissue function, thereby accelerating biological ageing processes. In parallel, accumulating evidence implicates epigenetic modifications, including changes in DNA methylation, histone modifications, and non-coding RNA expression, as key mechanisms through which maternal nutritional status exerts durable effects on gene expression and disease susceptibility.
A novel CYP2E1 inhibitor, 4-Methyl-5-Acetylthiazole, mitigates LPS-induced acute lung injury by suppressing macrophage-mediated inflammation and preserving mitochondria.
Gao L, Wang M, Yang R … +8 more , Qiu J, Jia L, Deng M, Tang L, Wen Q, Xu H, Gao N, Qiao H
Free Radic Biol Med · 2026 Aug · PMID 42036092 · Publisher ↗
Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is characterized by pulmonary edema, inflammatory cell infiltration, and alveolar epithelial damage. Here, we investigated the protective effects of 4-Methyl-5-...
Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is characterized by pulmonary edema, inflammatory cell infiltration, and alveolar epithelial damage. Here, we investigated the protective effects of 4-Methyl-5-Acetylthiazole (Q11), a novel CYP2E1 inhibitor, against LPS-induced ALI. Q11 significantly reduced lung index, wet-to-dry ratio, histopathological injury, and bronchoalveolar lavage fluid protein and cell content in LPS-induced ALI mice, indicating a protective effect of Q11 against ALI. Mechanistically, Q11 suppressed CYP2E1 level and inhibited M1 macrophage polarization, reducing pro-inflammatory cytokines in lung tissue, bronchoalveolar lavage fluid, and serum. Additionally, Q11 mitigated oxidative stress, restored mitochondrial membrane potential and ATP production, balanced mitochondrial dynamics, and attenuated apoptosis in alveolar epithelial cells and macrophages. In vitro, Q11 did not directly protect epithelial cells from LPS-induced injury but indirectly improved epithelial viability and reduced apoptosis via modulation of macrophages in a conditioned medium co-culture system. Collectively, these findings demonstrate that Q11 protects against LPS-induced ALI by inhibiting CYP2E1-mediated M1 macrophage activation, alleviating oxidative stress, preserving mitochondrial function, and indirectly safeguarding epithelial cells. Our results suggest that Q11, as a novel CYP2E1 inhibitor, exhibits promising translational potential and represents a potential therapeutic strategy for ALI.
DECR1 degradation by ursolic acid alleviates vascular calcification through inhibition of NF-κB/NLRP3 signaling pathway.
Yang H, Chen A, Ye Y … +6 more , Zhou X, Li Y, Wen X, Du Z, Lan Z, Yan J
Free Radic Biol Med · 2026 Aug · PMID 42034130 · Publisher ↗
Vascular calcification is a common pathological feature in atherosclerosis, diabetes, chronic kidney disease and aging, and is associated with increased incidence of cardiovascular events and all-cause mortality. However...
Vascular calcification is a common pathological feature in atherosclerosis, diabetes, chronic kidney disease and aging, and is associated with increased incidence of cardiovascular events and all-cause mortality. However, effective treatments for vascular calcification remain lacking. Ursolic acid (UA), a naturally occurring compound abundantly found in apple peels and known for its potent anti-inflammatory properties, has not been previously explored in vascular calcification. In the present study, UA inhibited osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) in vitro, and reduced calcification in human arterial rings ex vivo. Furthermore, UA attenuated aortic calcification in chronic kidney disease (CKD) rats and vitamin D3-overloaded mice. Mechanistically, UA binds to 2,4-dienoyl-CoA reductase 1 (DECR1), leading to its degradation and the subsequent inhibition of NF-κB/NLRP3 signaling pathway. This resulted in reduced expression of downstream inflammatory mediators such as cleaved Caspase-1 and IL-1β. DECR1 expression was upregulated in calcified human VSMCs, arterial rings, and CKD rat aortas. DECR1 knockdown alleviated calcification, and its overexpression aggravated calcification in VSMCs and aortic rings. This study for the first time establishes the inhibitory effects of UA on vascular calcification by suppressing NF-κB/NLRP3 inflammasome pathway and identifies DECR1 as a key mediator in this process, offering new insights for potential therapeutic strategies.
Bovine serum albumin-coated metal-phenolic nanoplatform for atherosclerosis therapy via targeted delivery and inhibition of vascular smooth muscle cells proliferation.
Li N, Huang Q, Liu Y … +5 more , Ren D, Liu Y, Liu X, Zhang P, Liu R
Free Radic Biol Med · 2026 Aug · PMID 42034129 · Publisher ↗
Aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) are central drivers of atherosclerosis (AS). In this study, we developed novel metal-phenolic nanoparticles (ECG-Cu NPs) synthesized via coordi...
Aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) are central drivers of atherosclerosis (AS). In this study, we developed novel metal-phenolic nanoparticles (ECG-Cu NPs) synthesized via coordination between epicatechin gallate (ECG) and copper ions (Cu). Surface modification with bovine serum albumin (BSA) produced a biomimetic nanoplatform (BSA@ECG-Cu NPs) designed to exploit both the enhanced permeability and retention effect and the intrinsic inflammatory targeting ability of BSA for preferential accumulation at atherosclerotic lesions. In VSMCs, BSA@ECG-Cu NPs significantly suppressed excessive oxidative species generation. Mechanistic studies revealed that this antioxidative effect was mediated by modulation of the TLR4, MAPK, and NF-κB signaling pathways. The resulting alleviation of oxidative stress further activated cell cycle-related regulatory responses, effectively suppressing the aberrant VSMC proliferation by modulating the expression and phosphorylation of key proteins (Cyclin D1, p-Rb, and E2F1). In atherosclerotic ApoE mice, administration of BSA@ECG-Cu NPs effectively reduced plaque area, inhibited intimal hyperplasia, enhanced vascular stability, and alleviated oxidative stress. Furthermore, the treatment exhibited no significant systemic toxicity, indicating favorable biocompatibility. Collectively, this multifunctional nanoplatform integrates targeted delivery with multilevel regulation of antiproliferative signaling, offering a promising and translational therapeutic strategy for the treatment of AS.
Corrigendum to "Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-dependent mitophagy" [Free Radic. Biol. Med. (2025) 150-160].
Zhu L, Huang M, He L … +1 more , Rong Z
Free Radic Biol Med · 2026 Jul · PMID 42031652 · Publisher ↗
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Mitochondrial metabolism as a determinant of heterogeneous platelet functional phenotypes: Implications for antiplatelet resistance.
Franco CV, Araya-Maturana R, Fuentes E
Free Radic Biol Med · 2026 Aug · PMID 42031120 · Publisher ↗
Platelets are increasingly recognized as a heterogeneous circulating cell population whose functional behavior cannot be fully explained by receptor-agonist signaling alone; instead, their bioenergetic state emerges as a...
Platelets are increasingly recognized as a heterogeneous circulating cell population whose functional behavior cannot be fully explained by receptor-agonist signaling alone; instead, their bioenergetic state emerges as a molecular determinant that shapes both physiological hemostasis and disease-associated hyperreactivity. This review synthesizes evidence supporting energetic specialization in platelets, where glycolytic ATP predominantly supports rapid responses such as shape changes and aggregation; mitochondrial oxidative phosphorylation (OXPHOS) instead is critical for high-demand functions, particularly sustained granule secretion and thrombus amplification. Building on this framework, we propose that mitochondria act as a molecular "switch" that sets the threshold between an aggregatory phenotype and procoagulant fate, for which mitochondrial membrane potential (ΔΨm) instability and sustained opening of the mitochondrial permeability transition pore (mPTP) drive commitment to a procoagulant crisis. Mitochondrial quality-control pathways, including fission/fusion dynamics and mitophagy, emerge as a key regulator that preserve this threshold; their impairment increases susceptibility to stress and predisposes platelets to pathological activation. In cardiometabolic disorders (e.g., type 2 diabetes and obesity), mitochondrial remodeling, oxidative stress, and a shift toward a more glycolytic profile are associated with intrinsically heightened reactivity and pharmacodynamic failure manifesting as high on-treatment platelet reactivity (HTPR), underscoring the need for functional stratification. Collectively, these findings support a bioenergetically informed framework in which mitochondrial function defines platelet functional heterogeneity and contributes to thrombotic risk. Integrating platelet mitochondrial biology into translational research may enable improved risk stratification and the development of precision antithrombotic strategies that preserve essential hemostatic function.
Sex-Specific lipid peroxidation profile and clinical features in a cognitive impairment cohort.
Ferré-González L, Peña-Bautista C, López-Nogueroles M … +3 more , Durand T, Baquero M, Cháfer-Pericás C
Free Radic Biol Med · 2026 Aug · PMID 42031119 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) displays a sex imbalance; women represent two-thirds of cases and often progress faster. Lipid peroxidation contributes to AD neurotoxicity from the oxidation of fatty acids can. Howe...
BACKGROUND: Alzheimer's disease (AD) displays a sex imbalance; women represent two-thirds of cases and often progress faster. Lipid peroxidation contributes to AD neurotoxicity from the oxidation of fatty acids can. However, how sex modulates plasma lipid peroxidation across clinical stages remains poorly characterized. This study examines sex- and AD clinical stage-related patterns in these plasma compounds. METHODS: Plasma lipid peroxidation compounds were quantified by liquid chromatography/mass spectrometry in a clinical cohort stratified into 6 groups (cognitively unimpaired (without AD (n = 93), with AD (n = 27)), mild cognitive impairment (due to AD (n = 105), not due to AD (n = 45)), mild dementia (due to AD (n = 84), not due to AD (n = 34))). RESULTS: Across clinical groups, women showed a more severe clinical profile, while men showed higher neurofilament light chain (NfL) levels in several groups. Specifically, 10 lipid peroxidation compounds showed impaired levels in women with AD, while only 2 compounds in men. Notably, significant positive correlations were observed between certain lipid peroxidation compounds and cerebrospinal fluid (CSF) biomarkers exclusively in women. Positive correlations were observed between isoprostanes/neuroprostanes and some neuropyschological tests (CDR, MMSE, ADCS-ADL-MCI) in women, as well as mixed correlations between lipid peroxidation compounds and two tests (RBANS, FAQ) in men. Furthermore, multivariate analysis confirmed that clinical diagnosis was the main determining factor rather than biological sex, with 4 lipid peroxidation compounds (10-epi-10-F-NeuroP, 17-epi-17-F-dihomo-IsoP, total IsoP and total NeuroP) showing differences among clinical groups with distinct patterns of progression, specifically men showing higher levels in preclinical stages, while women showed more complex fluctuations throughout AD progression. CONCLUSIONS: Plasma lipid peroxidation follows sex-dependent biological patterns across clinical stages of AD, highlighting a wider variety of altered biomarkers in women, which underscores the need to evaluate sex-stratified approaches for the diagnosis and AD staging.
Neutrophil-derived reactive oxygen species and bystander tissue damage in inflammatory bowel disease.
Kim JY, Colgan SP, Cartwright IM
Free Radic Biol Med · 2026 Aug · PMID 42031118 · Publisher ↗
Neutrophils (PMNs) are indispensable effectors of innate immunity whose oxidative and proteolytic capabilities permit rapid microbial containment at mucosal surfaces. Nowhere is this more functionally consequential than...
Neutrophils (PMNs) are indispensable effectors of innate immunity whose oxidative and proteolytic capabilities permit rapid microbial containment at mucosal surfaces. Nowhere is this more functionally consequential than in the gastrointestinal tract, where PMN recruitment to the intestinal mucosa serves as both a critical antimicrobial safeguard and a primary driver of epithelial injury in inflammatory bowel diseases (IBD). Upon activation, PMNs deploy an intricate oxidative network centered on the phagocyte NADPH oxidase complex-derived superoxide and hydrogen peroxide in conjunction with the halogenating and nitrating chemistries catalyzed by myeloperoxidase (MPO). These pathways generate a rich repertoire of oxidants-including hypochlorous acid (HOCl), hypobromous acid, reactive nitrogen species, and secondary radical products-that interact with proteins, lipids, nucleic acids, and extracellular matrix components with distinct reaction kinetics and spatial preferences. Importantly, the magnitude, composition, and distribution of these oxidants shape tissue outcomes ranging from transient signaling alterations to epithelial barrier dysfunction and mutational injury contributing to dysplasia. Recent advances in redox proteomics, spatial transcriptomics, intravital imaging, and single-cell analyses have expanded our understanding of how PMN oxidative radical pathways operate within specific mucosal microenvironments and how their outputs intersect with epithelial repair pathways, the microbiome, innate immune crosstalk, and disease chronicity. These studies reveal that PMNs do not function as a uniform oxidative manner; rather, distinct subsets specialize in oxidative burst, extracellular trap formation, metabolic adaptation, or reparative functions. Together, these data emphasize that oxidative injury in IBD is not an unavoidable byproduct of inflammation but rather a dynamic, context-dependent process that with significant potential as a therapeutic target. In this review, we synthesize current knowledge of PMN oxidative radical biology with a focus on the gastrointestinal mucosa. We examine the architecture of PMN reactive oxygen species (ROS) systems, delineate mechanisms of oxidative tissue injury, integrate translational and microbiome implications, and evaluate therapeutic strategies aimed at reducing bystander damage while preserving essential host defense. Through this framework, we highlight future directions that may enable the development of selective redox-modulating therapies capable of restoring mucosal integrity without compromising antimicrobial function.
Diet-induced hepatic and mitochondrial lipid remodeling engages one-carbon metabolism under preserved mitochondrial function.
Carli F, Guerra S, Mateus I … +8 more , Ducoli R, Sabatini S, Pezzica S, Scoditti E, Dewalle C, Lenoir V, Prip-Buus C, Gastaldelli A
Free Radic Biol Med · 2026 Aug · PMID 42025706 · Publisher ↗
BACKGROUND: Diets rich in saturated fat and sugar drive hepatic steatosis, yet their impact on mitochondrial lipid composition and function remains poorly understood. We investigated how steatotic diets reprogram phospho...
BACKGROUND: Diets rich in saturated fat and sugar drive hepatic steatosis, yet their impact on mitochondrial lipid composition and function remains poorly understood. We investigated how steatotic diets reprogram phospholipid synthesis, remodel the hepatic mitochondrial lipidome, and affect mitochondrial energy metabolism. METHODS: Mice were fed a high-fat/high-sucrose (HFHS) diet for 20 weeks alongside controls. Lipidomics, metabolomics and metabolic flux analysis using deuterated water (HO) were performed via high-resolution mass spectrometry in plasma, liver, and isolated hepatic mitochondria. Mitochondrial respiration was assessed via high-resolution respirometry (OROBOROS). A second cohort was fed a methionine choline-deficient (MCD) diet as a model of altered one-carbon metabolism. RESULTS: HFHS feeding caused marked hepatic lipid accumulation and extensive remodeling of plasma, liver, and mitochondrial lipidomes, including reduced synthesis of select phosphatidylcholines (PCs). Mitochondrial PCs concentrations were tightly linked to dietary modulation of one-carbon metabolism, which governs PC biosynthesis via methylation. Despite these changes, the mitochondrial PC/PE ratio remained stable and mitochondrial respiration and energy metabolism were preserved. To further evaluate the role of one-carbon metabolism in mitochondrial PC, we evaluated changes during MCD feeding. MCD reduced total mitochondrial lipids, particularly PC and PE synthesis and the mitochondrial PC/PE ratio. Remarkably, mitochondrial function remained intact in both dietary conditions. CONCLUSION: Steatotic and PC-depleting diets induce substantial remodeling of mitochondrial phospholipids without compromising mitochondrial respiratory capacity. These findings highlight the central role of one-carbon metabolism as a key regulator of mitochondrial membrane homeostasis and underscore the adaptive resilience of mitochondria under dietary and pro-fibrotic stress.
Mitochondrial sulfide oxidation and persulfidation in mesenchymal stromal cell osteogenesis: Redox flux control as a unifying framework.
Ciaramellano D, Brunetti L, Sinjari B … +2 more , Murmura G, Ferrara E
Free Radic Biol Med · 2026 Aug · PMID 42025705 · Publisher ↗
Hydrogen sulfide (HS) regulates mitochondrial metabolism and thiol-dependent redox signaling. Central to its biological activity is mitochondrial sulfide oxidation, initiated by sulfide:quinone oxidoreductase (SQOR), whi...
Hydrogen sulfide (HS) regulates mitochondrial metabolism and thiol-dependent redox signaling. Central to its biological activity is mitochondrial sulfide oxidation, initiated by sulfide:quinone oxidoreductase (SQOR), which couples HS catabolism to electron transport and persulfide generation. While sulfide signaling has been extensively characterized in stress adaptation and metabolic regulation, its integration with stem-cell fate decisions remains incompletely defined. Osteogenic differentiation of mesenchymal stromal cells (MSCs) requires coordinated mitochondrial remodeling, tightly constrained reactive oxygen species (ROS) signaling, and redox-sensitive transcriptional control, including RUNX2 stability. Emerging evidence indicates that HS modulates these processes through persulfidation, respiratory modulation, and NRF2-dependent adaptation in a dose- and kinetics-dependent manner. We propose a redox-flux framework in which SQOR-dependent sulfide oxidation functions as a regulatory interface linking mitochondrial bioenergetics, reactive sulfur species signaling, and osteogenic lineage commitment. Translational relevance is discussed in relation to exposure paradigms, including sustained low-dose sulfide models, that may inform experimentally testable hypotheses on redox-adaptive osteogenesis.
Myeloperoxidase (MPO) mediates LPS-induced mitophagy in murine macrophages through AMPK/ULK1 pathway.
Lin W, Zeng Y, Li J … +6 more , Zhang X, Wang Z, Zhao D, Chen X, Zhang Y, Guo C
Free Radic Biol Med · 2026 Aug · PMID 42025704 · Publisher ↗
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GLUL deficiency causes sperm acrosome defects and male infertility via influencing redox balance in mice.
Lin M, Feng Y, Zhang Y … +4 more , Wang H, Wang Y, Feng N, He Q
Free Radic Biol Med · 2026 Aug · PMID 42025703 · Publisher ↗
Glutamate-ammonia ligase (GLUL) catalyzes the syntheses of glutamine, as the antioxidant that has been shown to influence sperm quality in mammals. Research on the precise functions of the GLUL gene during spermatogenesi...
Glutamate-ammonia ligase (GLUL) catalyzes the syntheses of glutamine, as the antioxidant that has been shown to influence sperm quality in mammals. Research on the precise functions of the GLUL gene during spermatogenesis has been constrained by the structural complexity of the testis. In this study, we established a mouse model with postnatal, germ cell-specific deletion of GLUL. Conditional knockout (cKO) of GLUL led to reduced male fertility. Epididymal sperm from cKO mice exhibited acrosomal malformation, diminished acrosin activity, and redox imbalance. Moreover, GLUL deficiency was found to alter protein levels of Spam1 and Tssk3 in epididymal sperm. These functional deficits could be partially rescued by intraperitoneal glutathione (GSH) administration or by intracytoplasmic sperm injection (ICSI). Collectively, our results demonstrate that GLUL in germ cells is essential for combating oxidative stress during spermatogenesis in mice. These findings enhance the understanding of GLUL's role in male germ cell development and propose GSH supplementation as a potential therapeutic strategy for conditions associated with low acrosin activity.
GpoA glutathione peroxidase links oxidative stress response, antibiotic persistence, and virulence in Streptococcus pneumoniae.
Zappia VE, Hernandez-Morfa M, Raya-Plasencia L … +3 more , Olivero NB, Cortes PR, Echenique J
Free Radic Biol Med · 2026 Aug · PMID 42025702 · Publisher ↗
Glutathione peroxidases are conserved enzymes found in prokaryotic and eukaryotic organisms that reduce HO to protect cells from oxidative stress damage. Here, we identified and characterized the GpoA glutathione peroxid...
Glutathione peroxidases are conserved enzymes found in prokaryotic and eukaryotic organisms that reduce HO to protect cells from oxidative stress damage. Here, we identified and characterized the GpoA glutathione peroxidase of Streptococcus pneumoniae, one of the most important human bacterial pathogens. We demonstrated that recombinant GpoA exhibits glutathione peroxidase activity and that the Cys residue is essential for this function. We conducted a comparative analysis of the phenotypic characteristics linked to GpoA and those linked to other peroxidases, including the TpxD thiol peroxidase and the AhpD alkylhydroperoxidase. We analyzed a mutant strain lacking the gshT gene, which encodes the GSH-binding protein component of the glutathione ABC transporter complex. The ΔgpoA, ΔtpxD, ΔahpD, and ΔgshT mutants exhibited increased susceptibility to HO, and also impaired intracellular survival in pneumocytes, macrophages, and neutrophils compared to the wild-type strain. These results indicate that GpoA, TpxD, and AhpD constitute a robust HO detoxification system. Our findings further demonstrate that GpoA contributes to levofloxacin persistence under oxidative stress conditions, both in HO-treated cultures and during intracellular infection. Similar phenotypic patterns were observed in the ΔtpxD and ΔahpD mutants, indicating that antibiotic persistence depends on the oxidative stress response. In a murine model, the ΔgpoA mutant exhibited diminished survival across multiple organs relative to the wild-type strain, suggesting that GpoA contributes to pneumococcal pathogenesis. This study demonstrates that GpoA functions as an efficient antioxidant enzyme integral to the oxidative stress response in S. pneumoniae, facilitating the bacterium's survival both extracellularly and intracellularly under oxidative stress conditions.
SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.
Wang Z, He J, E J … +2 more , Yang Y, Yang X
Free Radic Biol Med · 2026 Aug · PMID 42019765 · Publisher ↗
Accumulating evidence indicates that mitochondrial dysfunction is a hallmark of cancer. Nonetheless, the mechanisms linking mitochondrial dysfunction to cancer progression remain largely elusive. SLC25A48 was recently re...
Accumulating evidence indicates that mitochondrial dysfunction is a hallmark of cancer. Nonetheless, the mechanisms linking mitochondrial dysfunction to cancer progression remain largely elusive. SLC25A48 was recently recognized as a transporter involved in mitochondrial choline uptake. Nevertheless, the roles of SLC25A48 in human malignancies remain unexplored. Here, we found that SLC25A48 is elevated in colorectal cancer (CRC) tissues and associates with unfavorable patient outcomes. Functional analyses showed that SLC25A48 accelerates the growth of CRC by enhancing proliferative capacity and preventing cell death. Mechanistically, SLC25A48 exerts its oncogenic function by enhancing the synthesis of choline-derived betaine, which is an important source of one-carbon units for numerous biosynthetic processes. On the one hand, SLC25A48 mitigates oxidative stress-induced ferroptosis by augmenting NADPH availability. On the other hand, it enhances cell proliferation by promoting mitochondrial energy production through upregulating mitochondrial DNA (mtDNA) replication and transcription. Importantly, silencing of SLC25A48 augmented the responsiveness of CRC cells to RSL3-induced ferroptosis and 5-FU-based chemotherapy. Furthermore, increased CTCF expression may contribute, at least in part, to the upregulation of SLC25A48 in CRC. Collectively, our data emphasize that SLC25A48 plays a critical oncogenic role in CRC and holds potential as a druggable target to overcome drug resistance in CRC.
ZIP4 protects against CCl-induced liver fibrosis by regulating zinc homeostasis, oxidative stress, and ferroptosis.
Luo J, Yu Z, Gao J … +6 more , Zhao Y, Zhang B, Luo K, Jianggewaer Y, Wang S, Lu Z
Free Radic Biol Med · 2026 Aug · PMID 42019764 · Publisher ↗
Liver fibrosis is a progressive pathological process driven by chronic liver injury, with limited effective therapies. Zinc transporter ZIP4 (SLC39A4) is critical for zinc homeostasis, but its role in liver fibrosis rema...
Liver fibrosis is a progressive pathological process driven by chronic liver injury, with limited effective therapies. Zinc transporter ZIP4 (SLC39A4) is critical for zinc homeostasis, but its role in liver fibrosis remains unclear. Here, we show that ZIP4 expression is significantly downregulated in fibrotic human liver tissues. Using hepatocyte-specific Zip4 knockout and AAV8-mediated ZIP4 overexpression mouse models, we demonstrate that ZIP4 deficiency exacerbates CCl-induced liver injury, fibrosis, oxidative stress, apoptosis, and ferroptosis, whereas ZIP4 overexpression alleviates these lesions. Mechanistically, ZIP4 maintains hepatic zinc homeostasis, upregulates antioxidant enzymes (PRDXs, SODs), and inhibits ferroptosis by regulating p53, SLC7A11, SLC40A1, and GPX4. Furthermore, zinc gluconate (Zn-Glu) combined with GCN2 inhibitor (GCN2iB) synergistically increases ZIP4 expression and intracellular zinc levels in HepG2 cells. In CCl-treated mice, Zn-Glu plus GCN2iB upregulates hepatic ZIP4, enhances antioxidant capacity, suppresses ferroptosis, and mitigates liver fibrosis. Collectively, our findings identify ZIP4 as a novel anti-fibrotic regulator that protects against liver fibrosis by maintaining zinc homeostasis, restraining oxidative stress, and inhibiting ferroptosis. The Zn-Glu/GCN2iB combination exerts anti-fibrotic effects by activating ZIP4 signaling, representing a promising strategy for clinical intervention.
Advanced oxidation protein products exacerbate osteoarthritis progression by disrupting stress granules assembly via endoplasmic reticulum stress.
Jiang W, Wang Q, Zhang X … +4 more , Qi B, Liang Y, Li D, Yi C
Free Radic Biol Med · 2026 Aug · PMID 42009145 · Publisher ↗
Recent studies indicate that levels of Advanced Oxidation Protein Products (AOPPs) in the synovial fluid of osteoarthritis (OA) patients positively correlate with disease severity. AOPPs are not only biomarkers of oxidat...
Recent studies indicate that levels of Advanced Oxidation Protein Products (AOPPs) in the synovial fluid of osteoarthritis (OA) patients positively correlate with disease severity. AOPPs are not only biomarkers of oxidative damage but also effector molecules that drive disease progression. Although stress granules (SGs) play a central role in cellular stress response, their function in AOPPs-mediated OA progression remains unclear. This study is the first to reveal the signaling pathway through which AOPPs exacerbate OA by disrupting SGs assembly. We found that AOPPs disrupt intracellular calcium homeostasis, induce endoplasmic reticulum stress (ERS), and subsequently activate the PERK-ATF4-CHOP signaling axis. This activation upregulates the key regulator GADD34. Increased GADD34 leads to abnormal dephosphorylation of eIF2α, which hinders the nucleocytoplasmic transport of the core SGs protein TIA-1 and ultimately disrupts SGs assembly. Further experiments demonstrated that the GADD34-specific inhibitor Sephin1 effectively restores eIF2α phosphorylation and rebuilds SGs formation, significantly alleviating OA progression. Moreover, we innovatively developed a hyaluronic acid microneedles transdermal delivery system loaded with Sephin1. In vivo studies confirmed that its efficacy is comparable to intra-articular injection, while offering the advantages of being minimally invasive and safe. This research not only elucidates a novel mechanism of the AOPPs-ERS-SGs axis in OA pathogenesis but also provides a new therapeutic target and delivery strategy for OA treatment.
DLAT sustains redox homeostasis and prevent colorectal cancer from ferroptosis by regulating SLC25A39-mediated mitochondrial glutathione transport.
Zhang K, Zhang X, Huang C … +5 more , Yang J, Dong L, Chen X, Xun C, Guo Y
Free Radic Biol Med · 2026 Aug · PMID 42009144 · Publisher ↗
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with limited therapeutic options for advanced-stage patients. Here, we identify DLAT, a key enzyme in mitochondrial metabolism, as a critical d...
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with limited therapeutic options for advanced-stage patients. Here, we identify DLAT, a key enzyme in mitochondrial metabolism, as a critical driver of CRC progression. Multi-omics analyses revealed that DLAT was overexpressed in CRC tissues and correlated with poor patient prognosis. The results showed that DLAT promoted CRC growth by promoting the resistance to mitochondrial antioxidant stress and suppressing ferroptosis. Mechanistically, DLAT directly bond to the mitochondrial glutathione (mtGSH) transporter SLC25A39 and enhanced its protein stability independent of intracellular GSH levels, leading to the maintain of mitochondrial GSH (mtGSH) import and redox homeostasis. Knockdown of DLAT or SLC25A39 disrupted mtGSH transport, elevated lipid peroxidation, and sensitized CRC cells to ferroptosis. We further identified a small molecular drug GL-V9 as a DLAT degrader. GL-V9 bond to DLAT and induced DLAT degradation through ubiquitin-proteasome pathway. The disruption of DLAT-SLC25A39 axis by GL-V9 led to mtGSH depletion and oxidative stress, as well as the significant suppression of CRC growth. These findings establish DLAT as a metabolic vulnerability in CRC and highlight GL-V9 as a promising therapeutic agent.
Prolactin drives the pathogenic amplification of atopic dermatitis by promoting CCL17 secretion through activation of the PI3K/AKT pathway.
Li Y, Li Z, Chen J … +7 more , Sui Y, Liu L, Zhou J, Du W, Zhao R, Yong L, Liu S
Free Radic Biol Med · 2026 Aug · PMID 42009143 · Publisher ↗
BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder driven by a combination of epidermal barrier dysfunction, immune dysregulation, and psychological stress. Although neuro-endocrine-...
BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder driven by a combination of epidermal barrier dysfunction, immune dysregulation, and psychological stress. Although neuro-endocrine-immune interactions are known to contribute to the pathogenesis of AD, the key endocrine mediators and their molecular mechanisms require elucidation. Prolactin (PRL), a stress-associated hormone with cytokine-like immunomodulatory properties, has not been fully characterized in the context of AD. METHODS: This study integrated analyses of clinical samples, an MC903-induced AD-like mouse model, primary keratinocyte functional assays, and keratinocyte-specific Prlr conditional-knockout (CKO) mice. PRL/PRL receptor (PRLR) expression, inflammatory cytokine levels, and histopathological changes were assessed using RNA sequencing (RNA-seq) analysis, gene set enrichment analysis, and western blotting, immunofluorescence, and flow cytometry analyses to delineate the underlying mechanisms. In vivo interventions, including inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway and CC chemokine ligand 17 (CCL17) neutralization, were employed to evaluate their roles in PRL-mediated inflammatory responses. RESULTS: Patients with AD and AD-like mice exhibited markedly elevated PRL and PRLR levels, and PRL concentrations were positively correlated with disease severity and indicators of psychological stress. PRL activated the PI3K-AKT-nuclear factor kappa B (NF-κB) pathway and upregulated CCL17 expression in keratinocytes in vitro and exacerbated MC903-induced dermatitis in vivo by increasing interleukin (IL)-4, IL-13, and thymic stromal lymphopoietin (TSLP) levels. In contrast, Prlr-CKO mice showed attenuated skin inflammation and reduced Th2 cytokine expression upon MC903 stimulation. RNA-seq further revealed significant enrichment of the PI3K-AKT pathway in PRL-treated skin, with CCL17 being the most strongly upregulated chemokine. Neutralization of CCL17 markedly alleviated dermatitis and reduced Th2 cell infiltration, confirming the essential role of CCL17 in PRL-driven inflammation. CONCLUSION: This study provides the first systematic evidence showing that the PRL/PRLR signaling axis amplifies AD-like skin inflammation by activating the PI3K-AKT-NF-κB pathway and inducing CCL17 expression, thereby promoting Th2-driven immune responses. Thus, keratinocyte-expressed PRLR is a central hub linking stress responses to cutaneous inflammation, and both PRLR and CCL17 represent promising therapeutic targets for AD, particularly in stress-associated disease phenotypes.
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