Antioxidants & redox signaling最新文献

{"title":"The Ferroptosis-Immunity Axis in Diabetic Kidney Disease: Emerging Therapeutic Targets.","authors":"Wen Zhang, Sumei Xu, Zhijian Cao, Wei Zhou, Zhili Huang, Shihua Deng, Qiuju Zhou, Xiaoran Wang","doi":"10.1177/15230864261483982","DOIUrl":"https://doi.org/10.1177/15230864261483982","url":null,"abstract":"<p><strong>Significance: </strong>Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. Its burden continues to increase despite advances in glycemic and blood pressure control. This persistent risk highlights the need for therapeutic strategies that address injury-amplifying mechanisms beyond conventional metabolic and hemodynamic pathways. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a contributor to renal injury in DKD. However, its precise role in human disease is incompletely defined.</p><p><strong>Recent advances: </strong>Ferroptosis is closely linked to lipid peroxidation-derived danger signals that promote innate immune activation, including M1 macrophage polarization, neutrophil infiltration, dendritic-cell maturation, TLR4 signaling, and NLRP3 inflammasome activation. Ferroptotic cells release damage-associated molecular patterns, including HMGB1, which activate inflammatory cascades. In turn, inflammatory cytokines disrupt iron homeostasis, increase oxidative stress, and further sensitize renal cells to ferroptosis, forming a self-amplifying ferroptosis-immunity feedback loop.</p><p><strong>Critical issues: </strong>Candidate biomarkers, including GPX4 depletion, ACSL4 expression, lipid peroxidation products, interleukin-18, and NLRP3 activation, may support earlier risk assessment and patient stratification. However, clinical validation is limited, and standardized biomarker thresholds, longitudinal human data, renal-cell-specific targeting, and long-term safety data are still lacking.</p><p><strong>Future directions: </strong>Therapeutic strategies under investigation include ferroptosis inhibitors, iron chelators, GPX4-directed approaches, TLR4/NLRP3-targeted immunomodulators, kidney-targeted nanoparticles, and CRISPR-based modulation of ferroptosis regulators. Multiomics profiling and artificial intelligence may further support rational combination therapies. Targeting the ferroptosis-immunity axis alongside optimal glycemic control may provide a complementary mechanism-based strategy to delay DKD progression. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261483982"},"PeriodicalIF":6.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox Rewiring in Nicotine-Driven Gastric Carcinogenesis: Uncovering ROS-Dependent Oncogenic Circuits.","authors":"Xilei Liu, Qinhan Jiang, Boxuan Xie, Zhongwei Zhang, Jianming Zhou, Tong Zhou, Huai Wang","doi":"10.1177/15230864261483986","DOIUrl":"https://doi.org/10.1177/15230864261483986","url":null,"abstract":"<p><strong>Significance: </strong>Nicotine from tobacco products, secondhand smoke, and emerging delivery systems remains a major but underappreciated driver of gastric carcinogenesis (GC). Although reactive oxygen species (ROS) have long been implicated in tumor biology, current models incompletely explain how chronic nicotine selectively reprograms gastric epithelial signaling. This review advances the concept of redox rewiring, whereby nicotine establishes a persistent oxidative state that orchestrates multiple oncogenic programs <i>via</i> spatially compartmentalized NOX signaling.</p><p><strong>Recent advances: </strong>We synthesize evidence for a unified model wherein nicotine activates nAChR/β-AR signaling, Ca²⁺ influx, PKC, and compartmentalized NOX-derived ROS to generate distinct oncogenic outputs. Beyond the established NOX/ROS/NF-κB/MAPK-driven IL-8 and MMP-9 axes, we integrate emerging evidence into three interconnected modules governing EMT/metastasis (ABL1/STAT3/COX-2/periostin), survival/chemoresistance (ERK/GLI1/Bcl-2), and invasion/immune evasion (miR-21/PDCD4). Collectively, these circuits suggest that ROS function not merely as damaging byproducts but as spatially organized signaling mediators dictating tumor behavior.</p><p><strong>Critical issues: </strong>A major challenge is distinguishing established mechanisms from incompletely validated models. The three proposed axes are testable hypotheses requiring experimental validation. Most data derive from <i>in vitro</i> studies with nonphysiologic nicotine concentrations, and artifacts from nonspecific ROS probes are common. Compensatory pathway activation and multi-target effects of natural products remain underexplored.</p><p><strong>Future directions: </strong>We outline a precision-redox oncology roadmap linking pathway-specific biomarkers, mechanistically matched natural products, and biomarker-enriched trials. Priorities include genetic validation of the three axes, time-resolved ROS imaging, and pulsed natural product regimens. By reframing nicotine-driven GC as adaptive redox network remodeling, this review provides a framework for prevention, stratification, and next-generation therapy. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261483986"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Old Friends, New Faces in Endothelial Dysfunction and Senescence.","authors":"Niloofar Ale-Agha, Philipp Jakobs, Anne Rafflenbeul, Wiebke M Meyer, Simone Prömel, Judith Haendeler, Joachim Altschmied","doi":"10.1177/15230864261424882","DOIUrl":"10.1177/15230864261424882","url":null,"abstract":"<p><strong>Significance: </strong>Onset and progression of cardiovascular diseases are tightly linked to the aging process. Aging results in structural and functional changes including endothelial dysfunction and senescence, thereby impairing vascular functions. The molecules involved in these processes are far from understood.</p><p><strong>Recent advances: </strong>The cellular redox homeostasis and proteostasis as well as mitochondrial functionality play key roles in the maintenance of the endothelium and are impaired in senescence and aging. Over the last few years, several proteins, which were previously ascribed functions in other pathways and/or cellular compartments, have been shown to be involved in the regulation of these processes. These include G protein-coupled receptors, chaperones in the endoplasmic reticulum, and the proteins cyclin-dependent kinase inhibitor 1B/p27^KIP1 and telomerase reverse transcriptase, which were assigned previously unknown functions in the mitochondria. Based on the specific functions of these proteins, modulation of their signaling pathways, activity or subcellular localization, might provide leads for new therapeutic approaches targeting aging-associated endothelial dysfunction and vascular diseases.</p><p><strong>Critical issues: </strong>The proteins described in this review undoubtedly have functions in endothelial cells and the vasculature. However, before they are considered as potential therapeutic targets, potential side effects in other cell types and tissues should be critically investigated. This might be most important for proteins, which have diverging functions in different compartments of a cell.</p><p><strong>Future directions: </strong>Although several new pathways affecting endothelial functionality have been identified and might be of therapeutic relevance, further research is required to fully understand the exact molecular mechanisms. <i>Antioxid. Redox Signal.</i> 45, 297-314.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"297-314"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial NAD⁺ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.","authors":"Xiaorong Wang, Yuxin Li, Jinhua Tan, Xiaona Sun, Qidi Zhou, Rui Xu, Xiaoqi Song, Yu Cui, Zhaolong Zhang","doi":"10.1177/15230864261455714","DOIUrl":"10.1177/15230864261455714","url":null,"abstract":"<p><strong>Aims: </strong>Cerebral ischemia-reperfusion (I/R) injury is a leading cause of neurological disability and is characterized by mitochondrial dysfunction and oxidative stress. Although depletion of nicotinamide adenine dinucleotide (NAD⁺) is a hallmark of ischemic injury, therapeutic strategies aimed at NAD⁺ replenishment have shown limited efficacy. Whether impaired mitochondrial NAD⁺ import contributes to neuronal vulnerability after I/R remains poorly understood.</p><p><strong>Results: </strong>We found that cerebral I/R disrupts the balance of NAD⁺ distribution between the cytoplasm and mitochondria in the cortex due to upregulated expression of SLC25A51. Augmenting SLC25A51 expression restored mitochondrial NAD⁺ pools, improved mitochondrial respiratory function, reduced oxidative lipid damage, and attenuated neuronal injury. In contrast, SLC25A51 deficiency exacerbated mitochondrial dysfunction and heightened susceptibility to I/R stress. These effects occurred independently of global NAD⁺ biosynthesis, indicating that mitochondrial NAD⁺ transport rather than NAD⁺ availability <i>per se</i> is a critical determinant of neuronal survival.</p><p><strong>Innovation: </strong>This study reveals the subcellular distribution change of NAD⁺-mediated by SLC25A51 and its neuroprotective effects <i>via</i> modulating mitochondrial function after cerebral I/R injury.</p><p><strong>Conclusion: </strong>This study identifies defective mitochondrial NAD⁺ import as a previously underrecognized mechanism of cerebral I/R injury. By establishing SLC25A51-dependent NAD⁺ trafficking as a key regulator of mitochondrial redox balance and neuronal resilience, our findings shift the therapeutic paradigm from NAD⁺ supplementation to restoration of subcellular NAD⁺ distribution, highlighting mitochondrial NAD⁺ transport as a promising target for ischemic brain injury. <i>Antioxid. Redox Signal.</i> 45, 359-375.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"359-375"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the IKKα/NF-κB Axis with SGEC-Derived Exosomal miR-23b-3p Rebalances Treg/Th17 Immunity in Sjögren's Syndrome.","authors":"Yan Cai, Xianzhen Wang, Jing Feng, Changyong E","doi":"10.1177/15230864261443868","DOIUrl":"10.1177/15230864261443868","url":null,"abstract":"<p><strong>Background: </strong>Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by chronic inflammation, oxidative stress, and progressive salivary gland dysfunction. Current therapies remain limited in efficacy.</p><p><strong>Aim: </strong>This study explored the regulatory effect of exosome (Exo)-transported miR-23b-3p on the IκB kinase alpha (IKKα)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis in SS.</p><p><strong>Methods: </strong>Key SS-related microRNAs (miRNAs) were identified by integrating weighted gene co-expression network analysis with machine-learning-based transcriptomic profiling. Target genes and functional pathways were analyzed by bioinformatics methods. The direct binding between miR-23b and IKKα (CHUK) was validated by a dual-luciferase reporter assay. An <i>in vitro</i> SS cell model was established to examine the effects of miR-23b-3p on the IKKα/NF-κB pathway, oxidative stress, inflammation, and apoptosis. miR-23b-3p was loaded into salivary gland epithelial cell-derived Exos (SGEC-Exos) <i>via</i> electroporation. <i>In vitro</i> coculture experiments assessed reactive oxygen species (ROS) levels, inflammatory cytokines, Treg/Th17 balance, and cell apoptosis. <i>In vivo</i> effects were evaluated in NOD/Ltj mice by measuring salivary flow rate, histopathology, and expression of salivary-function-related proteins AQP5 and GPER.</p><p><strong>Results: </strong>SGEC-Exos@miR-23b-3p significantly suppressed IKKα expression and NF-κB activation, reduced ROS production, and modulated immune responses by restoring the Treg/Th17 balance. It also inhibited apoptosis by decreasing Bax and caspase-3 expression and increasing Bcl-2 levels. These effects were partially reversed by reactivation of the IKKα/NF-κB pathway. In NOD/Ltj mice, SGEC-Exos@miR-23b-3p improved salivary flow, alleviated glandular pathology, and upregulated AQP5 and GPER expression.</p><p><strong>Conclusions: </strong>SGEC-Exos@miR-23b-3p offers a translational approach to address oxidative stress, immune imbalance, and glandular injury in SS, highlighting the potential of Exo-based miRNA therapy. <i>Antioxid. Redox Signal.</i> 45, 376-396.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"376-396"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP2A-ERK-PPAR-α/PGC-1α Axis Drives Tubular Lipotoxicity and Mitochondrial Dysfunction in Nephron-Sparing Surgery-Related Acute Kidney Injury.","authors":"Haoxun Zhang, Guoling Zhang, Bowen Wang, Feng Xiong, Xuran Ji, Chunyang Wang","doi":"10.1177/15230864261455422","DOIUrl":"10.1177/15230864261455422","url":null,"abstract":"<p><strong>Aims: </strong>Nephron-sparing surgery (NSS) is associated with acute kidney injury (AKI) that can accelerate chronic kidney disease progression, yet the mechanisms driving NSS-related injury (NRI) remain incompletely understood. In particular, how surgical stress reprograms proximal tubular energy metabolism independent of persistent ischemia remains unresolved. This study aimed to elucidate the mechanisms underlying lipid metabolic dysregulation and mitochondrial dysfunction in NRI.</p><p><strong>Results: </strong>Clinical cohort analysis showed that prolonged warm ischemia time was independently associated with postoperative AKI. Across human and experimental NRI, proximal tubular cells exhibited consistent suppression of fatty acid oxidation, increased lipid accumulation, and mitochondrial dysfunction. These metabolic abnormalities were associated with increased protein phosphatase 2A (PP2A) activity, reduced extracellular signal-regulated kinase (ERK) phosphorylation, and diminished transcriptional activity of the peroxisome proliferator-activated receptor-alpha (PPAR-α)/PGC-1α metabolic axis. Experimental modulation of PP2A or restoration of ERK-dependent PPAR-α signaling partially rescued mitochondrial function, reduced lipotoxic stress, and attenuated tubular injury. Single-cell and cell-type-resolved analyses localized these changes predominantly to metabolically active proximal tubular subpopulations, supporting the cell-type specificity of this pathway.</p><p><strong>Innovation and conclusion: </strong>This study identifies PP2A-dependent suppression of ERK-PPAR-α/PGC-1α signaling as a central mechanism underlying proximal tubular metabolic failure in NRI. By linking surgical stress to disordered lipid metabolism, these findings reveal a previously underappreciated regulatory pathway distinct from classical ischemic injury and highlight tubular metabolic resilience as a therapeutic target for mitigating kidney injury following nephron-sparing surgery. <i>Antioxid. Redox Signal.</i> 45, 315-337.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"315-337"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Collapse in Acute CNS Injury: A Spatiotemporal Framework Linking Redox Failure, Ferroptosis, and Neurovascular Dysfunction.","authors":"Liang Cao, Wang Zhao, Yanjun Zhang, Chunyu Hu, Leiluo Yang, V Wee Yong, Mengzhou Xue","doi":"10.1177/15230864261455615","DOIUrl":"10.1177/15230864261455615","url":null,"abstract":"<p><strong>Significance: </strong>Acute central nervous system (CNS) injuries impose a significant global burden. Microsurgical decompression effectively stabilizes primary anatomy. However, it often fails to stop the complex biochemical cascades of secondary neurodegeneration. There is a critical need to bridge the gap between anatomical preservation and functional recovery. Strong preclinical evidence indicates that delayed bioenergetic failure within the injury microenvironment heavily dictates long-term outcomes.</p><p><strong>Recent advances: </strong>We synthesize the ARFE (autophagy-reactive oxygen species-ferroptosis-edema) axis as a mechanistic framework delineating the pathological continuum from subcellular failure to macroscopic tissue edema. In this irreversible cascade, adenosine triphosphate depletion blocks autophagic flux, forcing ferritinophagy-driven iron release and lipid peroxidation, while succinate accumulation locks microglia in metabolic collapse.</p><p><strong>Critical issues: </strong>A translational gap persists because mechanical hematoma evacuation does not inherently reverse the metabolic cascades driving secondary injury. Current single-target modalities fail because they do not account for the evolving metabolic microenvironment, leading to unchecked inflammation and cell death despite successful surgical intervention.</p><p><strong>Future directions: </strong>We propose a paradigm shift from single-target modalities to \"spatiotemporal metabolic engineering.\" This strategy synchronizes interventions with metabolic logic. Hyperacute treatments focus on redox containment to neutralize iron. Acute phases prioritize immune-metabolic reprogramming for inflammation. Finally, subacute stages aim for bioenergetic reconstruction to support axonal regrowth. <i>Antioxid. Redox Signal.</i> 45, 397-412.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"397-412"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin-GHSR Attenuation, POMC Neuronal Modulation, and CD4⁺ T Cell Metabolic Reprogramming.","authors":"Xin Li, Ren-Yi Zhang, Wei-Hui Liu","doi":"10.1177/15230864261455465","DOIUrl":"10.1177/15230864261455465","url":null,"abstract":"<p><strong>Objective: </strong>Sleeve gastrectomy (SG) improves obesity-associated type 2 diabetes mellitus (T2DM) beyond mere weight loss. We investigated whether SG enhances systemic metabolic homeostasis by suppressing the Ghrelin-growth hormone secretagogue receptor (GHSR) axis, remodeling hypothalamic pro-opiomelanocortin (POMC) neuronal activity, and reprogramming CD4⁺ T cell immunometabolism.</p><p><strong>Methods: </strong>Using a diet-induced T2DM mouse model undergoing SG or Sham surgery, we integrated bulk/single-cell RNA sequencing and metabolomics to evaluate systemic neuro-immune-metabolic alterations. Functional assays validated Ghrelin's effects on CD4⁺ T cell metabolism and differentiation, alongside assessments of hepatic/pancreatic function and hypothalamic neuronal activity.</p><p><strong>Results: </strong>SG globally remodeled peripheral immunity, expanding Tregs while reducing pro-inflammatory Th17 cells. scRNA-seq and metabolomic profiling revealed that CD4⁺ T cells shifted metabolically from glycolysis toward oxidative phosphorylation, matching increased tricarboxylic acid cycle intermediates. Functionally, Ghrelin-GHSR signaling promoted CD4⁺ T cell glycolysis, mitochondrial damage, and Th17 skewing; GHSR antagonism successfully reversed these detrimental effects. Systemically, SG reduced hyperglycemia and hepatic lipidosis, restored islet α/β-cell balance, activated anorexigenic POMC neurons, and suppressed AgRP neurons.</p><p><strong>Conclusion: </strong>SG alleviates T2DM through coordinated suppression of the Ghrelin-GHSR axis, bridging central appetite regulation with peripheral immunometabolic reprogramming. By shifting CD4⁺ T cells toward oxidative metabolism and restoring the Treg/Th17 balance, SG drives systemic metabolic recovery, providing critical molecular insights into the neuro-immune mechanisms of metabolic surgery. <i>Antioxid. Redox Signal.</i> 45, 338-358.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"338-358"},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.","authors":"Jin Liu, Aiwei Wu, Jieyu Ling, Liquan Hong, Mingwei Wang, Xinyi Chen, Jianpin Zhou, Zhenyu Ju, Yue Sheng, Hongguang Xia, Hu Wang","doi":"10.1177/15230864261475098","DOIUrl":"https://doi.org/10.1177/15230864261475098","url":null,"abstract":"<p><strong>Aims: </strong>Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy <i>via</i> the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity.</p><p><strong>Results: </strong>We identified MCL-1 as the most highly expressed mitophagy receptor in aged HSCs. Treatment with UMI-77, a selective MCL-1 agonist, significantly enhanced mitophagy, reduced mitochondrial mass, improved mitochondrial membrane potential, and reduced reactive oxygen species levels in aged HSCs both <i>in vitro</i> and <i>in vivo</i>. Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes (<i>Sqstm1</i>, <i>Fundc1</i>, <i>Bnip3</i>) and restored stemness signatures in long-term HSCs. Transplantation assays demonstrated that UMI-77-treated aged HSCs exhibited superior hematopoietic reconstitution capacity compared with those from control mice. However, this intervention also increased the proportion of myeloid-biased CD150^high HSCs, a hallmark of aging.</p><p><strong>Conclusion: </strong>Targeted mitophagy restoration <i>via</i> MCL-1 activation improves mitochondrial fitness and stemness in aged HSCs but does not reverse myeloid bias. These findings highlight mitophagy enhancement as a viable therapeutic approach, while suggesting combinatorial strategies may be needed to fully restore lineage balance in aging hematopoiesis. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261475098"},"PeriodicalIF":6.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cystathionine β-Synthase Suppresses NLRP3 Inflammasome Activation <i>via</i> Redox Regulation in Microglia.","authors":"Yu-Jie Mou, Ya-Ting Ma, Xin Yuan, Miao Wang, Yang Liu, Chong-Shuang Pei, Chun-Feng Liu, Xiao-Ou Hou, Li-Fang Hu","doi":"10.1089/ars.2022.0174","DOIUrl":"10.1089/ars.2022.0174","url":null,"abstract":"<p><strong>Aims: </strong>Cystathionine β-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H₂S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H₂S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD.</p><p><strong>Results: </strong>Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H₂S generation were found in the brains of microglial <i>cbs</i> conditional-knockout (<i>cbs</i> ^cKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial <i>cbs</i> ^cKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas <i>cbs</i> overexpression or activation produced opposite effects. <i>In vitro</i> studies showed that <i>cbs</i> overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1β secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of <i>cbs</i> enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger.</p><p><strong>Innovation and conclusion: </strong>The study demonstrated an elevated GSSG level and reduced H₂S generation, which correlated with a susceptible status of microglia in the brain of <i>cbs</i> ^cKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"198-218"},"PeriodicalIF":6.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10150030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}