Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Metabolic energy expenditure in human blood long-lived neutrophils reprogrammed with inflammatory cytokines.
Breton Y, Gignac J, Lam TK … +6 more , Fortin CM, Mortazavi H, Allaeys I, Bourgoin SG, Poubelle PE, Pelletier M
Free Radic Biol Med · 2026 Aug · PMID 42097321 · Publisher ↗
The development of new analytical tools has revealed the heterogeneity of neutrophils in healthy and diseased subjects. Knowledge of this heterogeneity has led to the identification, in healthy individuals, of a minor su...
The development of new analytical tools has revealed the heterogeneity of neutrophils in healthy and diseased subjects. Knowledge of this heterogeneity has led to the identification, in healthy individuals, of a minor subset of blood neutrophils that express anti-protease genes characteristic of in vivo long-lived neutrophils, similar to those we previously described in vitro, which are expanded in autoimmune diseases. We can reprogram normal human blood neutrophils in vitro using GM-CSF, TNF, and IL-4, resulting in long-lived (LL) cells with enhanced glycolysis and oxygen consumption. We further report that these LL neutrophils express numerous genes associated with metabolism and mitochondria, including PLPP3 and SLC25A27. In addition, we confirmed that LL neutrophils express anti-peptidase genes, the most expressed being the PI3 gene, and secrete the peptidase inhibitor elafin and the secretory leukocyte protease inhibitor. Extracellular flux analysis revealed that PI3-expressing LL neutrophils exhibit enhanced glycolysis and respiration in response to pro-inflammatory cytokines, whereas non-reprogrammed neutrophils remain unresponsive. PI3-expressing LL neutrophils have a mitochondrial respiration partly driven by pyruvate oxidation, as demonstrated by the use of an inhibitor of mitochondrial pyruvate carrier. In contrast, oxygen consumption in control neutrophils was driven by fatty acid oxidation, as shown by the effect of inhibiting carnitine palmitoyltransferase 1. Thus, the reprogramming of neutrophils with GM-CSF, TNF, and IL-4 into cells capable of producing peptidase inhibitors is associated with an original metabolic phenotype characterized by active mitochondrial pathways.
ROS, identified as a driver for fibroblast activation, can be counteracted by glucocorticoid in LINC00605-dependent GMD machinery.
Zhu H, Zhu L, Zhang J … +12 more , Luo Y, Zhang J, Shao X, Feng X, Yan L, Zhang L, Ning H, Li B, Peng H, Li Y, Bai W, Li J
Free Radic Biol Med · 2026 Aug · PMID 42097320 · Publisher ↗
Fibroblast-to-myofibroblast transformation embodies a central facet of fibroblast activation, evidenced by elevated α-SMA levels and increased extracellular matrix synthesis. While excessive reactive oxygen species (ROS)...
Fibroblast-to-myofibroblast transformation embodies a central facet of fibroblast activation, evidenced by elevated α-SMA levels and increased extracellular matrix synthesis. While excessive reactive oxygen species (ROS) are traditionally viewed as drivers of oxidative stress-related damage, emerging data implicate ROS in the pathological transformation of certain fibroblast subsets. However, the precise contributions of raised ROS to fibroblast activation remain to be defined. In this study, employing single-cell RNA sequencing and hypertrophic scars as a model of phenotypic transition, we demonstrate that elevated ROS promotes fibroblast transition to the myofibroblast state, marked by excessive proliferation and collagen synthesis. Conversely, ROS inhibition attenuates this phenotypic shift. Notably, glucocorticoids-classically anti-inflammatory agents-were found to suppress ROS generation in hypertrophic scar-derived fibroblasts (HSFBs). This effect is mediated by downregulation of NOXA1, a pivotal ROS-producing gene. Moreover, the glucocorticoid-mediated reduction of NOXA1 expression does not occur via the classical glucocorticoid receptor (GR) pathway but through a novel LINC00605-dependent glucocorticoid receptor-mediated mRNA degradation (GMD) mechanism. Mechanistically, GR binds NOXA1 mRNA, while glucocorticoid-induced upregulation of LINC00605 directly engages the GMD factor YBX1. The LINC00605-YBX1 complex is selectively recruited to NOXA1 mRNA via lncRNA-mRNA interactions, promoting GMD complex assembly and ultimately triggering NOXA1 mRNA decay. Collectively, these findings indicate that elevated ROS-driven fibroblast activation and intercellular phenotypic transitions can be reversed by glucocorticoids through ROS suppression, highlighting ROS-targeted strategies as promising approaches to mitigate hypertrophic scarring.
TSPO integrates redox and immune homeostasis in dermal fibroblasts to restrain vitiligo pathogenesis.
Lv J, Yin C, Yu W … +5 more , Jiang P, Xu W, Zhang H, Cao Y, Gao R
Free Radic Biol Med · 2026 Aug · PMID 42097319 · Publisher ↗
Vitiligo is a chronic depigmenting disorder characterized by oxidative stress-driven melanocyte loss and T cell-mediated immune activation. While melanocytes and keratinocytes have been extensively studied, the contribut...
Vitiligo is a chronic depigmenting disorder characterized by oxidative stress-driven melanocyte loss and T cell-mediated immune activation. While melanocytes and keratinocytes have been extensively studied, the contribution of dermal fibroblasts to the oxidative and immune microenvironment remains unclear. Here, we identify the mitochondrial translocator protein (TSPO) as a key regulator of redox, inflammatory, and adhesion signaling in dermal fibroblasts. TSPO expression was markedly upregulated in both HO-treated fibroblasts and skin biopsies from vitiligo patients, suggesting a compensatory response to oxidative injury. TSPO deficiency aggravated mitochondrial dysfunction, lipid peroxidation, and apoptosis, while its overexpression restored mitochondrial potential, ATP production, and calcium homeostasis. Mechanistically, TSPO activated the p62/Keap1/Nrf2/HO-1 pathway to enhance antioxidant defense and concurrently suppressed NF-κB, NLRP3, and STAT1 signaling, reducing the expression of pro-inflammatory mediators and adhesion regulators. Pharmacological activation of TSPO with the high-affinity ligand Ro5-4864 restored mitochondrial function, reinforced antioxidant capacity, and alleviated depigmentation in an HO-induced vitiligo mouse model, while also diminishing CD8 T cell infiltration and enhancing HO-1 expression. Our findings establish TSPO as a mitochondrial safeguard in dermal fibroblasts, integrating redox control and inflammatory restraint, and highlight TSPO ligands as promising therapeutics for vitiligo.
Polystyrene nanoplastics drive neuronal senescence via PP2A-B56γ-targeted p-Ebp1 dephosphorylation-mediated ribosome biogenesis dysfunction.
Gao YL, Wang MZ, Wang LL … +11 more , Du ZB, Xie YH, Xu WQ, Wang YH, Li RH, Guo DB, Zheng HY, Yao YL, Song YB, Lin ZN, Lin YC
Free Radic Biol Med · 2026 Aug · PMID 42097318 · Publisher ↗
Nanoplastics (NPs) exhibit neurotoxicity, yet the precise molecular mechanisms remain elusive. In this study, we established a human-relevant polystyrene nanoplastics (PS-NPs, 50 mg kg) oral exposure model in C57BL/6 mic...
Nanoplastics (NPs) exhibit neurotoxicity, yet the precise molecular mechanisms remain elusive. In this study, we established a human-relevant polystyrene nanoplastics (PS-NPs, 50 mg kg) oral exposure model in C57BL/6 mice in vivo and a neuro-immune microglial-neuron co-culture system (HMC-3/SH-SY5Y cells) in vitro to dissect these mechanisms. We demonstrate that PS-NPs exposure triggers microglial M1 activation and drives neuronal senescence. Mechanistically, PS-NPs activate the protein phosphatase 2A (PP2A)-B56γ subunit, which selectively dephosphorylates the ribosome biogenesis regulator ErbB3-binding protein 1 (Ebp1) at Ser335. This post-translational modification reduces Ebp1 nucleolar localization, suppresses 47S pre-ribosomal RNA transcription, and induces nucleolar stress. Consequently, the p53/p21 pathway is engaged, promoting neuronal senescence. Pharmacological inhibition of PP2A with LB-100 restored ribosome biogenesis, prevented neuronal senescence, and rescued cognitive deficits and neurodegenerative phenotypes in PS-NP-exposed mice. This is the first study to identify the PP2A-B56γ-p-Ebp1-ribosome biogenesis axis as a novel cascade mechanism driving PS-NP-induced neuronal senescence. Our findings offer a targetable strategy to mitigate nanoplastics-associated neurodegeneration.
Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation.
Zhao X, Wang J, Wang Z … +15 more , Du H, Li H, Wu T, Yang K, Xie L, Zhang M, Wang J, Li P, Lv C, Deng Y, Ji H, Zhang Y, Li X, Yuan Y, Du Z
Free Radic Biol Med · 2026 Aug · PMID 42092410 · Publisher ↗
Precise modulation of the inflammatory response is critical for clearing damaged cardiomyocytes and promoting tissue regeneration after myocardial infarction (MI). Transient receptor potential mucolipin 1 (TRPML1) is an...
Precise modulation of the inflammatory response is critical for clearing damaged cardiomyocytes and promoting tissue regeneration after myocardial infarction (MI). Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel involved in regulating lysosomal biogenesis, Fe homeostasis, and phagocytic function; however, its role in post-MI inflammation remains unclear. This study shows that TRPML1 was significantly downregulated at both the protein and transcriptional levels in mouse cardiac tissue on days 3 and 7 post-MI. Using genetic lineage tracing, we found that macrophage-specific overexpression of TRPML1 attenuated the M1-dominant inflammatory response while enhancing M2-mediated repair in the infarcted area, ultimately reducing infarct size and improving cardiac function. In vitro co-culture experiments further demonstrated that activating macrophage TRPML1 restored the viability and collagen synthesis capacity of cardiac fibroblasts impaired by lipopolysaccharide (LPS). Mechanistically, TRPML1 directly targets Voltage-Dependent Anion Channel 1 (VDAC1) and inhibits its oligomerization, thereby reducing oxidative stress and ferroptosis in macrophages, and blocking mitochondrial DNA (mtDNA) escape into the cytoplasm and the subsequent activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This inhibition significantly alleviated the downstream pro-inflammatory cytokine storm. Importantly, inhibition of VDAC1 oligomerization with NSC 15364 rescued the ferroptosis and cardiac inflammation phenotypes in macrophage-specific TRPML1 knockout (Mac-TRPML1 KO) mice post-MI. In summary, our study identifies macrophage TRPML1 as a key metabolic checkpoint that regulates post-MI repair by controlling macrophage ferroptosis and cardiac fibroblast activation. We propose that targeting the TRPML1-VDAC1-cGAS-STING signaling axis may serve as a novel therapeutic strategy for post-MI inflammation.
The role of 3-mercaptopyruvate sulfurtransferase in colorectal cancer progression and tumor angiogenesis.
Rouse KC, Törő G, Szaniszlo P … +8 more , Govar AA, Servantes BJ, Chao C, Szabo C, Phatak UR, Qiu S, Hellmich MR, Módis K
Free Radic Biol Med · 2026 Aug · PMID 42092409 · Publisher ↗
Research from our group and others suggests that 3-mercaptopyruvate sulfurtransferase (3-MST) regulates endothelial cell (EC) function by modulating angiogenic and bioenergetic responses and by stimulating colorectal can...
Research from our group and others suggests that 3-mercaptopyruvate sulfurtransferase (3-MST) regulates endothelial cell (EC) function by modulating angiogenic and bioenergetic responses and by stimulating colorectal cancer (CRC) cell proliferation. However, the role of 3-MST function in the pathophysiology of CRC-associated angiogenesis remains to be explored. In this study, we investigated the contribution of 3-MST to CRC-associated angiogenesis, blood vessel function, tumor growth, and tumor cell proliferation. We aimed to define the functional role of stable 3-MST attenuation in ECs using both in vitro angiogenesis assays and in vivo xenogeneic and syngeneic CRC mouse models. Our results show that 3-MST depletion in vitro, alone or in the presence of tumor cell-conditioned media , reduces EC proliferation, disrupts tube-like network formation, and increases monolayer permeability. In vivo, loss of 3-MST function, either in ECs co-injected with CRC cells into athymic nude mice or in the tumor microenvironment of syngeneic global 3-MST knockout mice, resulted in reduced tumor growth along with significantly reduced peritumor angiogenesis. These findings indicate that 3-MST plays a critical role in EC proliferation, tube formation, and barrier function, thereby enhancing tumor angiogenesis and ultimately affecting tumor progression, highlighting its potential as a therapeutic target for tumor-related vascular remodeling.
Oxidative stress inhibits milk fat production by p38 MAPK-Cebpα-Acsl6 axis in mouse mammary gland.
Wang X, Su J, Gao J … +7 more , Liu M, Sui F, Xie Y, Wang Z, Lin Y, Yang Y, Hou X
Free Radic Biol Med · 2026 Aug · PMID 42092408 · Publisher ↗
The high incidence of oxidative stress in mammals during lactation affects mammary gland health, milk yield, and milk quality. However, the molecular mechanisms underlying oxidative stress-induced mammary gland dysfuncti...
The high incidence of oxidative stress in mammals during lactation affects mammary gland health, milk yield, and milk quality. However, the molecular mechanisms underlying oxidative stress-induced mammary gland dysfunction remain unclear. The objective of the present study was to investigate the underlying molecular events in the decrease in milk fat production in mammary gland subjected to oxidative stress. We generated oxidative stress cell model by incubated mouse mammary epithelial cell line HC11 with 600 μM hydrogen peroxide (HO). HO incubation increased intracellular ROS content and MDA activity, but decreased SOD and CAT activities, as well as intracellular triglyceride (TG) content. We performed RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs) between HO-treated and control cells. 926 DEGs were identified, which included 457 up-regulated genes and 469 down-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the DEGs is involved in lipid metabolism, cell growth and death, and mitogen-activated protein kinase (MAPK) signaling pathway. Acyl-CoA synthetase long chain family member 6 (Acsl6) was positively regulated milk fat synthesis, while oxidative stress down-regulated Acsl6 expression. Ultimately, the mouse model of oxidative stress was established, and we verified the effect of oxidative stress on milk fat production in vivo. Overall, the results revealed oxidative stress activated the p38 MAPK pathway, downregulated the transcription factor CCAAT-enhancer-binding protein alpha (Cebpα), and inhibited the expression of Acsl6, thereby suppressing lipid droplets formation and reducing intracellular TG content. These findings elucidate the molecular mechanism underlying oxidative stress-mediated suppression of milk fat production, which may provide insights for the development of redox-targeted therapeutic strategies against oxidative stress-induced metabolic disorders.
Difenoconazole impairs male reproductive function by inducing spermatogenic ferroptosis via the Wnt/β-catenin/NCOA4-mediated ferritinophagy axis.
Zheng X, Guo Q, Wang R … +11 more , Zhao P, Li D, Liu X, Wang S, Huang X, Deng W, Wei Y, Shen L, Long C, Wu S, Wei G
Free Radic Biol Med · 2026 Aug · PMID 42092407 · Publisher ↗
Difenoconazole (DFZ), a widely used triazole fungicide, may pose a potential risk to male reproductive health, although its mechanistic basis in mammals remains incompletely understood. This study assessed DFZ-induced te...
Difenoconazole (DFZ), a widely used triazole fungicide, may pose a potential risk to male reproductive health, although its mechanistic basis in mammals remains incompletely understood. This study assessed DFZ-induced testicular injury through in vivo mouse models and in vitro GC-1 spermatogonia and GC-2 spermatocyte cell systems, conducting transcriptomic, metabolomic, and functional analyses concurrently. Chronic DFZ exposure was associated with dose-dependent testicular atrophy, disorganization of seminiferous tubule architecture, reduced sperm count, increased sperm malformation, and decreased serum testosterone levels, along with detectable DFZ accumulation in serum. Multi-omics profiling revealed coordinated molecular alterations in testicular tissue and germ cells, with ferroptosis-related pathways and lipid metabolic reprogramming being prominently enriched. In testicular tissue and germ cells, DFZ induced features consistent with ferroptosis, including depletion of GSH, accumulation of MDA and Fe, inactivation of GPX4, and mitochondrial damage. These changes were alleviated by Fer-1 and DFO, suggesting that ferroptosis contributes to DFZ-induced cytotoxicity. Moreover, GPX4 knockdown further aggravated DFZ-induced ferroptotic injury, supporting a central role for GPX4 in this process. Mechanistically, DFZ appeared to activate autophagy and NCOA4-mediated ferritinophagy, which may promote iron overload and lipid peroxidation. Wnt/β-catenin signaling activation reduced NCOA4 upregulation and ferroptotic damage, but this protective effect was nullified by NCOA4 silencing, suggesting NCOA4 operates downstream of Wnt/β-catenin signaling. These findings reveal that DFZ triggers spermatogenic ferroptosis through Wnt/β-catenin-NCOA4-mediated ferritinophagy, offering insights into triazole fungicide-induced male reproductive toxicity and highlighting potential targets for environmental infertility interventions.
TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation.
Chen Q, Zhou Y, Peng Y … +6 more , Lan J, Kang Y, Wu L, Liu J, Tang J, Peng Y
Free Radic Biol Med · 2026 Aug · PMID 42092406 · Publisher ↗
TAR DNA-binding protein 43 (TDP43) aggregation is a well-established pathological hallmark of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders, contributing significantly to oxidative stress an...
TAR DNA-binding protein 43 (TDP43) aggregation is a well-established pathological hallmark of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders, contributing significantly to oxidative stress and neuronal injury. Here, we report that the M337V mutation in TDP43 exacerbates its proteotoxicity relative to the wild-type protein. Concurrently, multi-omics analysis revealed a pronounced downregulation of TRIM16 in motor neuron-like cells expressing either wild-type or M337V mutant TDP43. Functional studies demonstrated that TRIM16 overexpression effectively mitigated oxidative stress, restored mitochondrial integrity, and suppressed ferroptosis. Mechanistically, TRIM16 promoted the ubiquitination and degradation of Keap1, thereby facilitating the activation of Nrf2-mediated antioxidant genes. Furthermore, we identified the iron import receptor TFR1 as a novel ubiquitination substrate of TRIM16. TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation. Collectively, our findings establish TRIM16 as a pivotal suppressor of TDP43-induced toxicity by orchestrating dual cytoprotective pathways to enhance cellular resilience, highlighting its promising therapeutic potential for TDP43 proteinopathy.
Corrigendum to "Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer" [Free Radic. Biol. Med. 43 (2007) 289-299].
Singh LP, Kundu P, Ganguly K … +2 more , Mishra A, Swarnakar S
Free Radic Biol Med · 2026 Jul · PMID 42086445 · Publisher ↗
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Erythropoietin signaling regulated by Rab26 attenuates sepsis-associated lung injury by suppressing macrophage ferroptosis via enhanced mitophagy.
Gong D, Zhu Z, Qin H … +7 more , Zhang M, Zhang W, Xiang Q, Qian H, He B, Zhang R, Wang G
Free Radic Biol Med · 2026 Aug · PMID 42086108 · Publisher ↗
Macrophage ferroptosis contributes to sepsis-associated acute lung injury (ALI); however, its upstream regulatory mechanisms remain poorly understood. Here, using a cecal ligation and puncture (CLP) murine sepsis model,...
Macrophage ferroptosis contributes to sepsis-associated acute lung injury (ALI); however, its upstream regulatory mechanisms remain poorly understood. Here, using a cecal ligation and puncture (CLP) murine sepsis model, we observed that macrophages from septic mice and bone marrow-derived macrophages (BMDMs) exposed to septic bronchoalveolar lavage fluid (BALF) exhibited concurrent suppression of EPOR expression and induction of ferroptosis. EPOR deficiency selectively reduced basal GPX4 expression and amplified ferroptotic cell death upon challenge with RSL3 or septic BALF. EPOR mice showed exacerbated sepsis-induced lung injury and mortality, which were rescued by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, EPOR deficiency downregulated PPARγ, which promotes GPX4 expression. EPOR deficiency also impaired PINK1-mediated mitophagy by reducing PINK1 but not PARKIN levels, while mitophagy induction attenuated ferroptosis in EPOR-deficient cells. rhEPO stimulation enhanced the EPOR/PPARγ axis and suppressed lipid peroxidation, whereas PPARγ antagonism inhibited PINK1 expression. We further identified Rab26 as a critical stabilizer of EPOR. Specifically, Rab26 deficiency upregulated the expression of BTRC, an E3 ligase that interacts with EPOR to promote its degradation. Consequently, Rab26 deficiency decreased EPOR levels, subsequently suppressing PPARγ and PINK1, thereby reducing GPX4 expression and blunting rhEPO-induced PINK1 upregulation. Collectively, EPOR signaling protects macrophages from ferroptosis by activating PINK1-mediated mitophagy in a Rab26-dependent manner. The Rab26-EPOR-PPARγ axis represents a promising therapeutic target for sepsis-induced lung injury.
Senp1 knockdown alleviates neuronal pyroptosis after subarachnoid hemorrhage by enhancing PINK1-mediated mitophagy.
Ma Y, Long H, Xiong H … +5 more , Cui S, Zhuang Y, Wei H, He Z, Tan J
Free Radic Biol Med · 2026 Aug · PMID 42082058 · Publisher ↗
BACKGROUNDS: Subarachnoid hemorrhage (SAH) is a critical condition in neurosurgery, and the severity of early brain injury (EBI) plays a pivotal role in determining patient outcomes. Recent studies have demonstrated that...
BACKGROUNDS: Subarachnoid hemorrhage (SAH) is a critical condition in neurosurgery, and the severity of early brain injury (EBI) plays a pivotal role in determining patient outcomes. Recent studies have demonstrated that neuronal pyroptosis occurs following SAH, aggravating neuroinflammatory damage and severely affecting prognosis. Small ubiquitin-like modifier (SUMO)-specific protease 1 (Senp1), a member of the SUMO protease family, is known to be involved in the regulation of neuroinflammation. However, whether Senp1 also modulates neuronal pyroptosis to influence neuroinflammation after SAH remains unclear. METHODS: A total of 284 male C57BL/6J mice were used to establish the SAH model via endovascular perforation. Fourteen days prior to modeling, an adeno-associated virus carrying Senp1 shRNA was injected into the lateral ventricles of the mice for gene knockdown. Additionally, primary neurons were treated with oxyhemoglobin to simulate the in vitro SAH environment. CCCP and PINK1 siRNA were applied to enhance and inhibit mitophagy, respectively. RESULTS: Senp1 primarily localized in cortical neurons, with its expression being significantly upregulated following SAH and peaking at 24 h. Its knockdown markedly alleviated brain edema and improved neurological function 24 h after SAH. Moreover, its downregulation reduced the neuronal expression of NLRP3 and cleaved GSDMD, as well as the production of IL-1β and IL-18, thereby attenuating neuroinflammation. Mechanistically, Senp1 knockdown enhanced PINK1-mediated mitophagy, reducing reactive oxygen species accumulation. CONCLUSIONS: Our findings suggest that Senp1 knockdown enhances mitophagy, thereby inhibiting NLRP3 inflammasome-mediated neuronal pyroptosis following SAH and improving EBI and neurological prognosis.
GCSH promotes MASH progression by regulating cuproptosis through the glycine-GSH metabolic pathway.
Fu X, Li Y, Chen J … +4 more , Yin B, Nasrin M, Huo R, Tian S
Free Radic Biol Med · 2026 Aug · PMID 42082057 · Publisher ↗
BACKGROUND AND OBJECTIVES: Cuproptosis, a recently identified form of programmed cell death, has an unclear role in the context of metabolic dysfunction-associated steatohepatitis (MASH). This study aims to elucidate the...
BACKGROUND AND OBJECTIVES: Cuproptosis, a recently identified form of programmed cell death, has an unclear role in the context of metabolic dysfunction-associated steatohepatitis (MASH). This study aims to elucidate the role of cuproptosis in the early stages of MASH progression, identify its primary regulatory factors, and delineate the associated molecular mechanisms. METHODS: Liver specimens from MASH patients were evaluated to characterize hepatic cuproptosis and its correlation with clinical indices. MASH cell models were established using free fatty acid (FFA)-treated primary hepatocytes and HepG2 cells, while an in vivo MASH model was induced by feeding mice a high-fat, high-fructose, high-cholesterol (HFFC) diet. The copper chelator tetrathiomolybdate (TTM) was administered to verify the causal role of cuproptosis. Bioinformatic analyses were conducted to identify core genes related to cuproptosis. Following shRNA-mediated gene knockdown, rescue experiments were performed using exogenous glycine supplementation and the GSH synthesis inhibitor buthionine sulfoximine (BSO). Comprehensive assessments were performed on cuproptosis markers, mitochondrial function, lipid metabolism, and inflammatory indicators. RESULTS: Hepatic cuproptosis was significantly activated in early-stage MASH patients and HFFC-fed mice, characterized by the depletion of Fe-S cluster proteins alongside robust DLAT oligomerization. These cuproptosis hallmarks showed positive associations with Non-Alcoholic Fatty Liver Disease Activity Scores (NAS) and metabolic dysfunction. Intervention with TTM substantially attenuated these changes and simultaneously improved mitochondrial respiratory chain function, reduced steatosis, and diminished inflammatory responses, thereby indicating that cuproptosis is a key driver of MASH pathology. Bioinformatic analysis identified the glycine cleavage system H protein (GCSH) as the core regulatory gene, which was significantly upregulated in liver tissues from both early-stage MASH patients and mouse models. Knockdown of Gcsh effectively suppressed cuproptosis and ameliorated MASH phenotypes. Mechanistically, we observed reduced hepatic glycine levels and decreased GSH/GSSG ratios in MASH. The upregulation of GCSH expression was observed to enhance glycine catabolism, consequently depleting the substrates necessary for GSH synthesis. Notably, rescue experiments mediated by BSO markedly diminished the protective effects of Gcsh knockdown, thereby corroborating the role of GSH as a pivotal downstream effector of GCSH within the glycine-GSH metabolic pathway. CONCLUSIONS: This study identifies cuproptosis as a critical pathogenic driver in the progression of early-stage MASH. We elucidate a novel GCSH-glycine-GSH-cuproptosis regulatory axis, wherein GCSH acts as an upstream metabolic regulator, rather than merely a passive substrate, exacerbating disease pathology through glycine catabolism-mediated GSH depletion. These findings suggest that GCSH and the glycine-GSH axis represent promising therapeutic targets for MASH intervention.
Taurine attenuates high-fat high-sugar diet-induced endoplasmic reticulum stress-mediated hepatocyte apoptosis.
Lin S, Song Y, Wang X … +9 more , Li C, Wang P, Gao S, Wang T, Qi Z, Wang Y, Rao Y, Zhao D, Yang J
Free Radic Biol Med · 2026 Aug · PMID 42070705 · Publisher ↗
High-fat and high-sugar diets lead to fat deposition and metabolic disorders in mammalian livers, causing chronic liver disease. The effect of high fat and high sugar on hepatocyte function is closely related to endoplas...
High-fat and high-sugar diets lead to fat deposition and metabolic disorders in mammalian livers, causing chronic liver disease. The effect of high fat and high sugar on hepatocyte function is closely related to endoplasmic reticulum stress. Taurine regulates lipid metabolism, reduces fat deposition and inhibits apoptosis. In this study, the relationship between taurine deficiency and taurine supplementation was investigated through both perspectives. The results showed that taurine synthesis rate-limiting enzyme deficiency could cause abnormal hepatic lipid metabolism, endoplasmic reticulum stress and hepatocyte injury. Taurine supplementation reduced blood glucose, hepatic endoplasmic reticulum stress and hepatocyte apoptosis. In short, taurine reduced hepatocyte apoptosis by attenuating hepatic endoplasmic reticulum stress.
AKR1C3-driven restoration of tetrahydrobiopterin synthesis in cellular sepiapterin reductase deficiency.
Woodcock J, Tan S, Vasquez-Vivar J
Free Radic Biol Med · 2026 Aug · PMID 42066821 · Publisher ↗
Sepiapterin reductase (SPR) catalyzes several key steps in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases, and therefore for neurotran...
Sepiapterin reductase (SPR) catalyzes several key steps in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases and aromatic amino acid hydroxylases, and therefore for neurotransmitter production. Although several reductases-including carbonyl reductase 1 (CBR1), aldose reductase (AKR1B1), and AKR1C3-can substitute for SPR activity in vitro, their physiological significance remains unresolved. This study examines AKR1C3 as a component of an alternative BH4-generating pathway and evaluates its capacity to compensate for BH4 loss under diminished SPR activity. In vitro assays identified 2'-OXPH4 as the primary product of AKR1C3, redirecting pathway flux away from the canonical 1'-OXPH4 intermediate and the sepiapterin-salvage pathway. To assess the occurrence and efficiency of this route in cells, we generated SPR-knockout (SPR-KO) cell and evaluated pathway products in SPR-KO and wild-type (WT) backgrounds. In WT cells neither AKR1C3 nor SPR overexpression altered BH4 synthesis, indicating that neither enzyme is rate-limiting. In contrast, AKR1C3 increased BH4 levels in SPR-KO cells, while inhibiting sepiapterin production, revealing that AKR1C3 becomes functionally engaged only when SPR activity is decreased. Based on relative enzyme abundance, AKR1C3 and SPR exhibited comparable catalytic efficiency in this context. Importantly, AKR1C3-mediated BH4 production was sufficient to sustain tyrosine hydroxylase (TH) activity in SPR-KO cells, as demonstrated by L-DOPA formation. These findings establish AKR1C3-driven 2'-OXPH4 synthesis as a bona fide, inducible pathway capable of maintaining BH4 levels when SPR activity is limiting. This alternative path provides a compelling therapeutic target and introduces a new diagnostic consideration for patients with diminished SPR activity.
Free Nε-(carboxymethyl)-lysine promotes diabetic kidney disease progression via RAGE/NF-κB/NLRP3 pathway-mediated podocyte PANoptosis.
Zhang L, Chen L, Guo W … +6 more , Cai L, Zeng X, Liu Y, Kang C, Huang X, Fu W
Free Radic Biol Med · 2026 Aug · PMID 42066820 · Publisher ↗
Diabetic kidney disease (DKD) is the major cause of end-stage renal disease worldwide. PANoptosis, a newly identified form of inflammatory cell death, is closely associated with DKD development, though its mechanism in D...
Diabetic kidney disease (DKD) is the major cause of end-stage renal disease worldwide. PANoptosis, a newly identified form of inflammatory cell death, is closely associated with DKD development, though its mechanism in DKD is still uncertain. Our previous study found elevated serum levels of free Nε-(carboxymethyl)-lysine (CML), a significant advanced glycation end product, in patients with renal dysfunction. However, its diagnostic value and role in DKD and PANoptosis remain unclear. Here, we found that serum levels of free CML were elevated in DKD patients, having the potential for early diagnosis. In vitro, free CML stimulation of podocytes (MPC5 cells) led to significant oxidative stress and cell injury, marked by increased reactive oxygen species (ROS), lactate dehydrogenase release, IL-1β secretion, and apoptosis level. In vivo, free CML injection in db/m and db/db mice worsened renal function and podocyte injury. PANoptosis caused this injury, and related inhibitors alleviated cell injury from free CML. Mechanistically, free CML increased NLRP3 via the NF-κB pathway, promoting RIPK1-PANoptosome formation and triggering podocyte PANoptosis, as confirmed by NF-κB inhibitors (PDTC) and Nlrp3 knockdown. Molecular docking and rescue experiments with the RAGE antagonist (FPS-ZM1) confirmed that free CML induced PANoptosis through the ROS/NF-κB pathway via RAGE. FPS-ZM1 reduced CML-induced PANoptosis and slowed DKD progression in db/db mice. These findings indicate that free CML activates the RAGE/NF-κB/NLRP3 axis, promoting podocyte PANoptosis and DKD progression, offering potential diagnostic and treatment targets.
LMT328, a sulfiredoxin inhibitor, induces preferential cancer cell death and tumor regression via oxidative stress.
Lee GR, Kwon M, Kim T … +6 more , Chang H, Jang Y, Oh SH, Choi Y, Lee JS, Jeong W
Free Radic Biol Med · 2026 Aug · PMID 42066819 · Publisher ↗
Cancer cells are more susceptible to oxidative damage due to their reliance on tightly regulated redox homeostasis. Sulfiredoxin (Srx) is an antioxidant enzyme that restores hyperoxidized peroxiredoxins and contributes t...
Cancer cells are more susceptible to oxidative damage due to their reliance on tightly regulated redox homeostasis. Sulfiredoxin (Srx) is an antioxidant enzyme that restores hyperoxidized peroxiredoxins and contributes to cellular redox regulation. Previously, we demonstrated that pharmacological inhibition of Srx induces preferential death of cancer cells and tumor regression by weakening antioxidant defenses. In this study, we investigated the anticancer efficacy of LMT328, a more potent Srx inhibitor developed through molecular modeling. LMT328 exhibited greater efficacy than the previously reported inhibitor J14 in inhibiting cellular Srx activity, elevating intracellular oxidative stress, inducing mitochondrial damage, and triggering apoptotic cell death in cancer cells. These effects were attenuated by ectopic Srx expression or antioxidant treatment, supporting that LMT328 exerts its cytotoxic effects through oxidative stress resulting from Srx inhibition. Notably, LMT328 induced greater oxidative stress, mitochondrial damage, and cytotoxicity in tumorigenic T80H cells compared with nontumorigenic T80 cells. In a xenograft model, LMT328 significantly suppressed tumor growth with minimal toxicity. Collectively, our findings demonstrate that LMT328 disrupts Srx-dependent redox homeostasis, leading to oxidative stress-associated mitochondrial damage and cancer cell death, and suggest that targeting Srx may represent a promising strategy for redox-based cancer therapy.
Targeted delivery of nebivolol via lactoferrin-modified liposomes inhibits NEK7-mediated pyroptosis to ameliorate inflammatory bowel disease.
Yao H, Yang L, Zhang Y … +8 more , Wu Q, Xie K, Liu H, Yao B, Jiang Z, Sun Q, Zeng Z, Yuan L
Free Radic Biol Med · 2026 Aug · PMID 42061481 · Publisher ↗
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder where pyroptosis of intestinal epithelial cells, driven by the NEK7/NLRP3 axis, is a key pathological feature. This study aimed to identify a novel inhi...
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder where pyroptosis of intestinal epithelial cells, driven by the NEK7/NLRP3 axis, is a key pathological feature. This study aimed to identify a novel inhibitor of NIMA-related kinase 7 (NEK7) and develop a targeted delivery system to enhance its therapeutic efficacy for IBD. Through a virtual screening of FDA-approved drugs, nebivolol was identified as a potent NEK7 inhibitor. Subsequent biochemical and cellular assays confirmed that nebivolol directly binds to the LYS64 site of NEK7, inhibiting its kinase activity and disrupting its interaction with NLRP3. This inhibitory action was shown to protect intestinal epithelial cells from pyroptosis in vitro and to significantly ameliorate disease symptoms, histological damage, and molecular markers of pyroptosis in a chronic DSS mouse model of colitis, with a high safety profile. To enhance therapeutic efficacy and specificity, a quantitatively characterized targeted delivery system of lactoferrin-modified liposomes loaded with nebivolol (LF-Lipo@N) was developed. This system demonstrated superior uptake by intestinal cells via lactoferrin and lactoferrin receptors (LFRs) interaction and a more potent anti-pyroptotic effect in vitro. Crucially, the quantitative biodistribution analysis showed that the targeted LF-Lipo@N system significantly accumulated in the colon in vivo, leading to a significantly enhanced therapeutic effect compared to free nebivolol while eliminating systemic side effects on heart rate. In conclusion, the targeted delivery of nebivolol via lactoferrin-modified liposomes represents a promising and effective strategy for treating IBD by specifically inhibiting NEK7-mediated intestinal pyroptosis.
Sesamol reprograms mitochondrial dysfunction and metabolic signaling to rescue endothelial degeneration in Fuchs' endothelial corneal dystrophy.
Nayak D, Kannan R, D'Souza S … +9 more , Shivakumar S, Shetty R, Shetty N, Malakar D, Machiraju P, Das D, Ghosh A, Deshpande V, Chakrabarty K
Free Radic Biol Med · 2026 Aug · PMID 42061480 · Publisher ↗
PURPOSE: Fuchs' endothelial corneal dystrophy (FECD) is a progressive corneal disease characterized by loss of corneal endothelial cells (CEnCs), eventually leading to blindness. Though mitochondrial dysfunction remains...
PURPOSE: Fuchs' endothelial corneal dystrophy (FECD) is a progressive corneal disease characterized by loss of corneal endothelial cells (CEnCs), eventually leading to blindness. Though mitochondrial dysfunction remains the central cause for endothelial cell death, its underlying metabolic drivers remain poorly defined. Hence, there is a need to investigate novel therapeutic approaches targeting metabolic dysregulation, rather than relying solely on surgical intervention. This study aims to explore the metabolic dysregulation in FECD and identify plausible novel non-invasive therapeutics. METHOD: Metabolomics was performed on aqueous humor (AH) obtained from FECD patients (n = 5). Corneal endothelial cells (iCEnCs) differentiated from induced pluripotent stem cells were exposed to oxidative stress using menadione (Mn) and assessed for barrier function, mitochondrial membrane potential, dynamics, biogenesis, mitophagy and apoptosis via immunofluorescence, qPCR and Western blot. Ex vivo human cadaveric corneal assays were done to evaluate CEnC barrier integrity and cell death. Potential therapeutic targets identified by AH metabolomics were further investigated using small molecule modulators for their ability to restore mitochondrial functionality. RESULTS: Metabolomics revealed depletion of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, sphingolipid imbalance and accumulation of xenobiotics in AH of FECD patients. Mn-treated iCEnCs revealed barrier breakdown (TEER ↓ 75%), mitochondrial depolarization (JC-1 ↓ 76 %), loss of Mfn2 (↓ 32 %) and PGC-1α (↓ 37%), accumulation of PINK1/Parkin and pro-apoptotic signaling mimicking FECD pathology. Gene expression of ion transport (SLC4A11), ECM genes (COL8A2) was down regulated, whereas expression of glycolytic genes (HK1 and GLUT1) showed upregulation. Supplementation with sesamol to Mn-treated iCEnCs most effectively restored mitochondrial potential (89% of control), normalized fusion-fission balance, reactivated PGC-1α and PPARγ, suppressed apoptosis (-85% BAX/Bcl2 ratio) and preserved barrier integrity. CONCLUSION: Sesamol not only rescued compromised endothelial cells but also effectively reinstated cellular metabolic homeostasis by mitigating underlying oxidative stress and rectifying mitochondrial signaling imbalances.
Vitamin D receptor/sirtuin 3 pathway mediates the cardioprotective effects of aerobic exercise in diabetic mice.
Cui XN, Li C, Qin YH … +6 more , Liu JJ, Jia CK, Sun XY, Lu SQ, Zhu Z, Cao ZB
Free Radic Biol Med · 2026 Aug · PMID 42061479 · Publisher ↗
Aerobic exercise ameliorates diabetic cardiomyopathy (DCM) by improving myocardial mitochondrial function; however, the underlying mechanisms remain unclear. Vitamin D alleviates DCM by upregulating vitamin D receptor (V...
Aerobic exercise ameliorates diabetic cardiomyopathy (DCM) by improving myocardial mitochondrial function; however, the underlying mechanisms remain unclear. Vitamin D alleviates DCM by upregulating vitamin D receptor (VDR) expression, and aerobic exercise also increases VDR expression. Whether VDR mediates the cardioprotective effects of aerobic exercise against DCM remains unknown. This study aims to probe whether aerobic exercise alleviates DCM by upregulating VDR. A DCM mouse model was established using male C57BL/6J mice via high-fat diet feeding and streptozotocin injection, while mice fed a standard diet served as controls. Cardiac-specific VDR knockdown and overexpression were achieved via recombinant adeno-associated virus-mediated delivery in diabetic mice. Diabetic mice were further subjected to vitamin D supplementation and exercise intervention. Additionally, H9C2 cardiomyocytes were exposed to high glucose and palmitate to mimic diabetic conditions in vitro. Notably, diabetic mice exhibited significant cardiac mitochondrial dysfunction, along with inflammation, fibrosis, and impaired cardiac function. However, vitamin D supplementation and aerobic exercise upregulated VDR expression and enhanced mitochondrial function, thereby alleviating the pathological manifestations of DCM in diabetic mice. VDR activation also mitigated high glucose and palmitate-induced mitochondrial dysfunction in H9C2 cardiomyocytes, but this effect was abrogated by sirtuin (SIRT)-3 inhibition. These results suggest that VDR promotes SIRT3-dependent enhancement of mitochondrial function, thereby alleviating DCM. Moreover, exercise-induced cardioprotective effects on mitochondrial function were impaired by cardiac-specific VDR knockdown but mimicked by cardiac-specific VDR overexpression. Overall, this study suggests that the VDR/SIRT3 axis is an essential mechanism mediating the cardioprotective effects of aerobic exercise against DCM.
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