Antioxidants & redox signaling最新文献

{"title":"Unlocking Sulforaphane's Potential in Friedreich Ataxia: Further Evidence from Preclinical Investigations Using Induced Pluripotent Stem Cell-Derived Sensory Neurons.","authors":"Wenyao Yang, Bruce Thompson, Sara Miellet, Marnie Maddock, Marek Napierala, Mirella Dottori, Faith A A Kwa","doi":"10.1177/15230864261470377","DOIUrl":"10.1177/15230864261470377","url":null,"abstract":"<p><strong>Aims: </strong>Friedreich ataxia (FRDA) is a neurodegenerative disorder typically caused by autosomal recessive inheritance of expanded guanine-adenine-adenine (GAA) repeats (>56) in both alleles of the frataxin (<i>FXN</i>) gene, leading to FXN protein deficiency. Omaveloxolone (Omav) is the only approved therapy. Therefore, further therapeutic options are essential. Previously, we showed that sulforaphane (SF) increases FXN expression and modulates epigenetic, inflammatory, and oxidative stress pathways in sensory neurons from a patient induced pluripotent stem cells (iPSCs) with 550 GAA1 repeats (FA2). Here, we compared SF, Omav, and dimethyl fumarate (DMF) treatment in sensory neurons derived from three patient iPSC lines with varying GAA1 repeats: FA1 (867), FA2, and FA3 (450).</p><p><strong>Results: </strong>In FA1, SF treatment improved cell viability and reduced oxidative stress and inflammation. In FA3, SF increased cell viability, FXN protein levels, and gene and protein expression of redox markers, while targeting dysregulated epigenetic mechanisms and inflammation. All three lines showed SF's consistent anti-oxidant and anti-inflammatory effects. Responses to Omav and DMF varied across the FA lines with less pronounced effects than when treated with SF. Overall, SF was more effective than Omav and DMF in improving cell viability and regulating FXN expression and epigenetic, redox, and inflammatory pathways.</p><p><strong>Innovation: </strong>These findings reveal variability in drug responses based on FRDA genetic profiles and position SF as a promising drug to address multiple pathological processes.</p><p><strong>Conclusion: </strong>Our preclinical data support SF as a strong FRDA drug candidate. Clinical evaluation is warranted to confirm its full therapeutic potential. <i>Antioxid. Redox Signal.</i> 45, 561-580.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"561-580"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519806","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":"Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.","authors":"Yueqing Yang, Ming Zhao, Yibo Feng, Hongli Yu, Yuanxin Gong, Qingqing Liu","doi":"10.1177/15230864261470736","DOIUrl":"10.1177/15230864261470736","url":null,"abstract":"<p><strong>Background: </strong>Cerebral ischemia-reperfusion injury (CIRI) is a key contributor to stroke-related neurological damage, but the functional interplay between autophagy and ferroptosis-two critical pathological processes-remains poorly understood.</p><p><strong>Methods: </strong>Using oxygen-glucose deprivation/reperfusion in PC12 cells and middle cerebral artery occlusion (MCAO) in rats, we combined molecular, pharmacological, and imaging approaches to investigate how autophagy regulates the ferroptosis suppressor acyl-CoA synthetase long-chain family member 3 (ACSL3).</p><p><strong>Results: </strong>Ischemia-reperfusion triggered hyperactivated autophagy, which promoted ferroptosis by selectively targeting ACSL3 for degradation <i>via</i> the autophagy receptor neighbor of BRCA1 gene 1 protein (NBR1). We further identified that tripartite motif-containing protein 33 (TRIM33), an E3 ubiquitin ligase induced after ischemia, directly ubiquitinates ACSL3 and facilitates its proteasomal degradation. This ubiquitin-mediated pathway acted synergistically with autophagy to control ACSL3 stability. Pharmacological inhibition of autophagy with curcumin derivative 5g (CUR5g) restored ACSL3 protein levels and suppressed ferroptosis. In MCAO rats, CUR5g-administered alone or in combination with the ferroptosis inhibitor Ferfluor-1-significantly improved functional recovery and reduced brain injury.</p><p><strong>Conclusion: </strong>Our study reveals a novel autophagy-NBR1/TRIM33-ACSL3 regulatory axis that drives ferroptosis in CIRI, highlighting a promising therapeutic strategy for ischemic stroke through cotargeting autophagy and ferroptosis. <i>Antioxid. Redox Signal.</i> 45, 676-692.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"676-692"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700513","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":"Unraveling Radiation Enteritis: Oxidative Stress as a Central Driver and Therapeutic Target.","authors":"Pengfei Zhong, Zhiyuan Li, Zhenjun Pu, Hongyu Nian, Junliang Li","doi":"10.1177/15230864261481021","DOIUrl":"10.1177/15230864261481021","url":null,"abstract":"<p><strong>Significance: </strong>Radiation enteritis (RE) is a prevalent complication following abdominopelvic radiotherapy (RT), significantly compromising patients' quality of life. Oxidative stress extends beyond merely mediating early tissue injury; it acts as the central regulatory axis orchestrating sequential pathological transitions, encompassing epithelial damage, immune activation, chronic ischemia, and fibrotic remodeling.</p><p><strong>Recent advances: </strong>RT-induced reactive oxygen species (ROS) burst provokes lipid peroxidation, mitochondrial dysfunction, programmed cell death, and epithelial barrier disruption. Subsequently, damage-associated molecular pattern release and microbial translocation propel immune-inflammatory amplification. Sustained ROS generation and ensuing inflammation further compromise the vascular endothelium, precipitating microcirculatory dysfunction and chronic hypoxia. Concurrently, barrier disruption and microbial dysbiosis form a feedback loop shifting sustained regenerative responses toward maladaptive repair, ultimately culminating in irreversible tissue remodeling.</p><p><strong>Critical issues: </strong>Pathogenically, RE is not simply a consequence of ROS overload, but an ROS-driven continuum of tissue state transitions resulting in regenerative failure. Furthermore, a \"redox paradox\" emerges wherein ROS concurrently drive normal intestinal injury and mediate RT's tumoricidal efficacy. Currently, regenerative failure and this redox paradox remain inadequately integrated into clinical paradigms for patient stratification, interventional timing, and efficacy evaluation.</p><p><strong>Future directions: </strong>Future endeavors must prioritize precision redox therapeutics characterized by tissue specificity, temporal regulation, and dose-dependent modulation. Leveraging targeted delivery, phased interventions, and biomarkers will reconcile the conflicting demands of normal tissue radioprotection and tumor control, propelling the paradigm shift from broad-spectrum antioxidants toward precision redox medicine. <i>Antioxid. Redox Signal.</i> 45, 596-617.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"596-617"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787311","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":"BACH2 Exacerbates Bronchopulmonary Dysplasia by Promoting NCOA4-Dependent Ferritinophagy via Transcriptional Activation of JUN.","authors":"Menghua Zhao, Yizhong Wu, Bufei Wu, Jun Xu, Duane Wang, Furong Huang, Aimin Zhang, Li Huang, Xu Wu","doi":"10.1177/15230864261471273","DOIUrl":"10.1177/15230864261471273","url":null,"abstract":"<p><strong>Aims: </strong>This study investigated whether BACH2 affects bronchopulmonary dysplasia (BPD) through ferritinophagy and elucidated its molecular mechanisms.</p><p><strong>Results: </strong>JUN was identified as a key gene linking BPD and ferritinophagy, showing elevated expression in preterm neonates with BPD and in hyperoxia-exposed alveolar epithelial cells (MLE12). In the cellular BPD model, knockdown of either JUN or its upstream regulator, BACH2, inhibited hyperoxia-induced nuclear receptor coactivator 4 (NCOA4)-dependent ferritinophagy, accompanied by restored cell viability and mitigated oxidative stress, autophagy flux, and ferroptosis. Functional rescue experiments confirmed NCOA4 as the critical downstream effector of JUN, and JUN overexpression reversed the protective effects of BACH2 silencing. Mechanistically, BACH2 activates JUN transcription, thereby augmenting c-Jun phosphorylation and the activity of the downstream AP-1 complex. In a neonatal mouse BPD model, BACH2 knockdown attenuated hyperoxia-induced lung injury, improved alveolarization and vascular remodeling, and suppressed the BACH2/c-Jun/NCOA4 pathway, ferritinophagy, and ferroptosis in lung tissues.</p><p><strong>Innovation: </strong>This study delineates a novel pathogenic axis in which BACH2 drives ferritinophagy-mediated ferroptosis in BPD by transcriptionally upregulating JUN, which, in turn, promotes NCOA4-dependent ferritinophagy, highlighting BACH2 and c-Jun as potential therapeutic targets.</p><p><strong>Conclusion: </strong>BACH2 exacerbates BPD by transcriptionally activating JUN, which promotes NCOA4-dependent ferritinophagy and ferroptosis. Targeting this axis offers a potential therapeutic strategy for BPD. <i>Antioxid. Redox Signal.</i> 45, 693-713.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"693-713"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590253","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":"Reactive Oxygen and Reactive Nitrogen Species in Herpesvirus Infections: Mechanisms, Clinical Implications, and Therapeutic Opportunities.","authors":"Rodrigo Reyes-Ramírez, Areli J Navarro, Gerardo E Ortiz, Eduardo I Tognarelli, Dayesi López-Hernández, Sofia Henríquez, Benjamín Rodríguez, Claudia A Riedel, Alexis M Kalergis, Luisa F Duarte, Pablo A González","doi":"10.1177/15230864261470376","DOIUrl":"10.1177/15230864261470376","url":null,"abstract":"<p><p><i>Significance:</i> Herpesvirus infections are highly prevalent in the human population, causing a broad spectrum of diseases ranging from mild to severe that affect numerous tissues, although most infections remain asymptomatic. These viruses establish lifelong infections through latency and may reactivate at different frequencies, with or without clinical symptoms. To counteract microbial infections, host cells have evolved molecular mechanisms that interfere with viral replication, including the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS).<i>Recent Advances:</i> ROS and RNS are not merely antimicrobial products but also regulators of pathogen gene expression, immune modulation, and cell fate decisions, with excessive production leading to oxidative stress and cellular damage, among other effects. Notably, many viruses, including herpesviruses, modulate ROS and RNS production in infected cells to promote viral replication and evade the host immune response. <i>Critical Issues:</i> In this review, we examine the complex interplay between ROS, RNS, and herpesvirus infections. The available literature suggests (i) that herpesviruses from all three subfamilies exploit ROS and RNS as molecular switches for viral replication and immune evasion, (ii) that the specific ROS and RNS species and pathways hijacked by these viruses differ by subfamily, creating distinct and targetable redox vulnerabilities, and (iii) that antioxidant interventions selectively restoring physiological redox balances could represent efficacious antiviral strategies.<i>Future Directions:</i> Highlighting emerging therapeutic strategies that modulate redox balance to control viral replication and disease progression, this review underscores the need for mechanistic and controlled clinical studies to validate virus subfamily-tailored, redox-based antiviral approaches. <i>Antioxid. Redox Signal.</i> 45, 636-675.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"636-675"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560707","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":"A Glucocorticoid-KLF9-CHCHD10 Axis Governs Mitochondrial Resilience in Radiation-Induced Lung Injury.","authors":"Peixin Tan, Kunpeng Wu, Mengsi Liu, Qinghua Zhang, Chen Ren, Shasha Du","doi":"10.1177/15230864261470735","DOIUrl":"10.1177/15230864261470735","url":null,"abstract":"<p><strong>Background: </strong>Radiation-induced lung injury (RILI) is a major dose-limiting complication of thoracic radiotherapy. Although mitochondrial damage has been implicated in RILI, the endogenous transcriptional programs that restore mitochondrial structure and bioenergetic function after irradiation remain poorly defined.</p><p><strong>Methods: </strong>To identify radiation-sensitive mitochondrial regulators in type II alveolar epithelial cells (AT2), we integrated single-cell RNA sequencing data from irradiated lungs with weighted gene co-expression network analysis. Transcription factor prediction, multi-omics correlation analysis, and molecular docking were used to construct upstream regulatory networks. The functional relevance of the KLF9-CHCHD10 axis was validated using mitochondrial ultrastructure analysis, oxygen consumption assays, apoptosis detection, gene expression profiling, and CHCHD10 loss- and gain-of-function experiments performed <i>in vitro</i> and <i>in vivo</i>.</p><p><strong>Results: </strong>Single-cell transcriptomic profiling identified CHCHD10, a mitochondrial cristae-associated protein, as a central radiation-sensitive hub in AT2 cells. Irradiation reduced CHCHD10 expression and disrupted mitochondrial homeostasis, leading to mitochondrial fragmentation, impaired oxygen consumption, enhanced epithelial apoptosis, activation of the Ppia-CD147 inflammatory signaling axis, and suppression of PPARγ-associated metabolic homeostasis. Mechanistically, KLF9 directly activated CHCHD10 transcription, whereas irradiation suppressed the KLF9-CHCHD10 circuit. Restoration of this pathway by CHCHD10 overexpression or glucocorticoid intervention preserved mitochondrial cristae integrity, improved bioenergetic recovery, and enhanced epithelial cell survival. <i>In vivo</i>, lung-specific CHCHD10 knockdown aggravated radiation-induced parenchymal remodeling and fibrotic deposition and partially weakened the protective efficacy of glucocorticoids.</p><p><strong>Conclusion: </strong>This study defines a GC-KLF9-CHCHD10 axis that restores mitochondrial ultrastructure and bioenergetics after radiation, positioning mitochondrial resilience as an active epithelial protective program in RILI. <i>Antioxid. Redox Signal.</i> 45, 581-595.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"581-595"},"PeriodicalIF":6.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560665","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":"Identification of Thioredoxin-Interacting Protein as an Upstream Regulator of Ferroptosis in Hyperuricemic Nephropathy.","authors":"Yuemei Xi, Qiang Wang, Yayan Liu, Shuai Huang, Mengni Wu, Shanpan Fu, De Xie, Jiayu Chen, Qian Zhang, Xueling Ye, Wanling Que, Shuyi Chen, Shiyu Lin, Meng Liang, Tetsuya Yamamoto, Hidenori Koyama, Jidong Cheng","doi":"10.1177/15230864261494911","DOIUrl":"https://doi.org/10.1177/15230864261494911","url":null,"abstract":"<p><strong>Aim: </strong>Hyperuricemic nephropathy (HN) is a major contributor to chronic kidney disease, yet current urate-lowering therapies often fail to halt tubular injury once established. While ferroptosis is known to drive renal injury in HN, the upstream molecular mechanisms remain unclear. We investigated whether thioredoxin-interacting protein (TXNIP) acts as an upstream regulator linking hyperuricemia to ferroptosis-associated tubular injury in HN.</p><p><strong>Methods: </strong>TXNIP expression was examined in renal biopsies from patients with HN and two murine models (drug-induced and <i>Uox</i>^-/- mice). Functional studies combined pharmacological suppression of TXNIP expression using verapamil with genetic validation in a novel <i>Uox</i>^-/-<i>Txnip</i>^-/- double-knockout model. Renal injury and ferroptosis-associated alterations were assessed using biochemical, molecular, histological, ultrastructural, and transcriptomic analyses.</p><p><strong>Results: </strong>TXNIP was markedly upregulated and predominantly localized to renal tubular epithelial cells in both murine models and patients with HN. Verapamil-associated suppression of TXNIP expression attenuated renal dysfunction, tubular injury, inflammation, and interstitial fibrosis without significantly reducing serum urate. The novel <i>Uox</i>^-/-<i>Txnip</i>^-/- model provided direct genetic evidence that TXNIP contributes to the hyperuricemic renal phenotype. Across the pharmacological and genetic approaches, renal protection was accompanied by reduced tubular iron accumulation and lipid peroxidation, restoration of glutathione (GSH) content and xCT/GPX4 expression, decreased ACSL4 expression, and attenuation of ferroptosis-associated mitochondrial abnormalities.</p><p><strong>Innovation and conclusion: </strong>These findings identify TXNIP as an upstream regulator of ferroptosis-associated tubular injury in HN and provide genetic evidence for its contribution to the hyperuricemic renal phenotype. The pharmacological findings further suggest that targeting TXNIP-associated injury pathways may complement conventional urate-lowering therapy. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261494911"},"PeriodicalIF":6.8,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126363","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":"Loss of Selenot in POMC Neurons Disrupts ER Homeostasis and Induces A Senescent-like Phenotype.","authors":"Cédric Jehan, Inès Drissa, Dorthe Cartier, Christine Bucharles, Azénor Abgrall, Agathe Prieur, Philippe Chan, Carole Burel, Marie-Laure Walet-Balieu, David Alexandre, Muriel Bardor, Christophe Dubessy, Youssef Anouar, Isabelle Lihrmann","doi":"10.1177/15230864261494912","DOIUrl":"10.1177/15230864261494912","url":null,"abstract":"<p><strong>Aims: </strong>Selenoprotein T (SELENOT) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase implicated in redox and calcium (Ca²⁺) homeostasis and protein quality control. Although SELENOT is highly expressed in the brain, its role in hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy balance, remains poorly understood. We investigated whether SELENOT is required for maintaining ER homeostasis and neuronal integrity in POMC neurons.</p><p><strong>Results: </strong>Using CRISPR-edited and siRNA-silenced POMC neuronal models together with a POMC-specific SELENOT knockout mouse, we demonstrated that SELENOT loss induces a senescent-like phenotype including cellular hypertrophy, loss of neurite outgrowth, senescence-associated β-galactosidase activity, increased P16 and P21 expression, and acquisition of senescence-associated secretory phenotype. Senescence markers were elevated not only in SELENOT-deficient POMC neurons but also throughout the surrounding arcuate nucleus <i>in vivo</i>, suggesting propagation of a pro-inflammatory microenvironment. Mechanistically, prolonged SELENOT deficiency produced selective activation of the ATF6α arm of the unfolded protein response, depletion of ER Ca²⁺ stores, and profound alterations in <i>N</i>-glycan maturation. Notably, leptin-induced POMC processing and secretion were spared. Glycomics revealed a shift toward immature glycans, whereas thiol-trapping proteomics identified candidate SELENOT interactors linked to ER Ca²⁺ regulation.</p><p><strong>Innovation and conclusions: </strong>This study provides the first evidence that SELENOT deficiency is sufficient to trigger cellular senescence in POMC neurons, acting as a central regulator integrating ER proteostasis, Ca²⁺ homeostasis, redox adaptation, and glycosylation. These results reveal a previously unrecognized mechanism potentially linking neuronal senescence to hypothalamic dysfunction and suggest that SELENOT-dependent pathways may represent therapeutic targets for obesity, metabolic disease, and age-related neuroendocrine disorders. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261494912"},"PeriodicalIF":6.8,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126404","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":"A SIRT1-PERK-HSPA5-MARCHF1 Proteostasis Axis Controls GPX4 Stability and Ferroptotic Susceptibility in Hepatic Stellate Cells.","authors":"Yixiao Wang, Huiya Ying, Hangu Wang, Jun Xu, Dandan Zhu, Hong Pan, Yuan Zeng, Xiangting Zhang, Ziqiang Xia, Ruoru Zhou, Xingyue Yu, Xiao Wu, Weimin Cai, Qian Zhao, Fujun Yu","doi":"10.1177/15230864261495029","DOIUrl":"https://doi.org/10.1177/15230864261495029","url":null,"abstract":"<p><strong>Aims: </strong>Liver fibrosis is a chronic inflammatory condition characterized by excessive extracellular matrix accumulation driven by hepatic stellate cell (HSC) activation, and inducing HSC ferroptosis represents an effective strategy to restrain fibrogenesis. In this study, liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of CCl₄ (10% in oil) twice weekly, and nodosin (1, 5, or 10 mg/kg/day) was administered by gavage starting 2 weeks after CCl₄ administration. This study aimed to evaluate the anti-fibrotic efficacy of nodosin, an ent-kaurane diterpenoid derived from the traditional Chinese medicinal herb Isodon serra, and investigate its mechanisms in CCl₄-induced liver fibrosis.</p><p><strong>Results: </strong>Our findings demonstrated that nodosin promotes HSC ferroptosis by regulating protein kinase R-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent glutathione peroxidase 4 (GPX4) proteostasis. Nodosin-mediated suppression of ATF4 reduced heat shock protein family A member 5 (HSPA5) expression, thereby enhancing the MARCHF1-GPX4 interaction and promoting K48-linked polyubiquitination and proteasomal degradation of GPX4. Mechanistically, HSPA5 restricted MARCHF1 access to GPX4, and K191 was identified as a functionally relevant ubiquitination site of GPX4. Nodosin also promoted SIRT1-mediated deacetylation of PERK at K1101, providing further mechanistic support for the regulation of PERK/ATF4 signaling.</p><p><strong>Innovation: </strong>This study identifies a previously unrecognized endoplasmic reticulum stress-proteostasis-ferroptosis regulatory axis in HSCs. We demonstrate that HSPA5 constrains MARCHF1-dependent K48 ubiquitination and degradation of GPX4, establishing GPX4 proteostasis as a key determinant of ferroptotic susceptibility during liver fibrogenesis. Nodosin modulates this axis through SIRT1-PERK signaling.</p><p><strong>Conclusion: </strong>Overall, nodosin alleviated CCl₄-induced liver fibrosis by promoting HSC ferroptosis. These findings reveal a proteostatic mechanism linking ER stress to GPX4 stability and ferroptotic susceptibility in HSCs. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261495029"},"PeriodicalIF":6.8,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126390","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":"A Unified Model of Cardiovascular Injury: How PANoptosis Connects Atherosclerotic Inflammation to Myocardial Death.","authors":"Xin Zhang, Mengdan Liu, Yunyun Yang, Gongliang Guo","doi":"10.1177/15230864261455539","DOIUrl":"10.1177/15230864261455539","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Significance: &lt;/strong&gt;Cardiovascular disease is traditionally viewed through fragmented lenses-atherosclerosis, ischemia-reperfusion injury, and heart failure as distinct entities. Emerging evidence positions PANoptosis, an integrated cell-death program combining pyroptosis, apoptosis, and necroptosis, as a unifying driver of inflammation and tissue destruction along the athero-myocardial axis. This synthesis reframes cardiovascular pathology as a continuum governed by shared immunometabolic triggers and coordinated cell-death machinery.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Recent advances: &lt;/strong&gt;We outline how upstream nucleic acid sensors, notably Z-DNA binding protein 1 (&lt;i&gt;ZBP1&lt;/i&gt;) and absent in melanoma 2, orchestrate PANoptosome assembly, engaging receptor-interacting protein kinase (RIPK)1, RIPK3, Caspase-8, gasdermin D (GSDMD), mixed lineage kinase domain-like, and executioner caspases to produce multimodal lytic death. In the vasculature, disturbed flow activates Piezo1-Calpain signaling. This mechanotransduction is proposed to lower the threshold for endothelial PANoptosis, partly through mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; overload, reactive oxygen species (ROS) generation, and mitochondrial DNA (mtDNA) release. Concurrently, macrophage uptake of oxidized lipids triggers a mitochondria-stimulator of interferon genes-GSDMD feed-forward loop. This process expands necrotic cores and destabilizes plaques. In ischemic myocardium, succinate-driven reverse electron transport generates a ROS burst during reperfusion, causing mtDNA release and &lt;i&gt;ZBP1&lt;/i&gt;-dependent PANoptosis in cardiomyocytes. This cascade propagates systemic inflammation through defective efferocytosis, bone-marrow trained immunity, and extracellular vesicle (EV) cargo transfer, ultimately driving fibrosis and heart failure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Critical issues: &lt;/strong&gt;Several conceptual and translational issues remain critical. Vascular and myocardial injuries may share core PANoptotic machinery, but they are linked systemically through inflammatory, metabolic, and immune feedback loops rather than by a simple linear cascade. Co-activation of pyroptosis, apoptosis, and necroptosis should be distinguished from true molecular shunting within PANoptosomes. Emerging EV-based propagation mechanisms require careful interpretation, and therapeutic windows differ across endothelial injury, plaque progression, reperfusion injury, and remodeling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Future directions: &lt;/strong&gt;Future strategies should prioritize nanomedicine-enabled precision delivery, metabolic reprogramming, and time-sensitive intervention across the athero-myocardial axis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Innovation: &lt;/strong&gt;This review proposes an athero-myocardial axis in which vascular and myocardial injuries share core PANoptotic machinery while being linked systemically through inflammatory, metabolic, and immune feedback loops. It differentiates co-activation from true molecular shunting within PANoptosomes, clarifies emerging EV-bas","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"456-473"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576560","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}