Antioxidants & redox signaling最新文献

{"title":"Melanin as a Redox Hub: Linking Energy Flow to Genome Stability and Immune Control.","authors":"Jyoti Srivastava, Sanjay Premi","doi":"10.1177/15230864261421542","DOIUrl":"10.1177/15230864261421542","url":null,"abstract":"<p><strong>Significance: </strong>Melanin is no longer best understood as a passive UV filter. It is emerging as a programmable, redox-active pigment system that converts environmental energy and oxidative stress into lasting genomic and immunological consequences, placing pigment metabolism at the center of melanoma biology.</p><p><strong>Recent advances: </strong>Oxidative melanogenesis activates nitric-oxide synthase (NOS), generating reactive nitrogen species that oxidize melanin fragments into electronically excited triplet carbonyls. These intermediates drive delayed cyclobutane pyrimidine dimers (dCPDs) hours after ultraviolet exposure, establishing a pigment-powered window of \"dark mutagenesis.\" In melanoma, this pigment-NOS-chemiexcitation axis forms a lineage-specific redox circuit linking oxidative metabolism to mutation density, nitrosylation signaling, and immune evasion. Genome-wide mapping further indicates that chemiexcitation concentrates damage within open, transcriptionally active chromatin.</p><p><strong>Critical issues: </strong>Key gaps remain in defining how pigment oxidation state, NOS flux, and subcellular organization coordinate chemiexcitation and nitrosylation in vivo, and how these processes reshape DNA repair and interferon programs across melanoma states. Parallels in neuromelanin, the retinal pigment epithelium, and mucosal pigment systems are provocative but require direct mechanistic validation.</p><p><strong>Future directions: </strong>Targeting pigment chemistry itself, through NOS inhibition, denitrosylation, and triplet-state quenching, offers a compelling translational strategy to suppress dCPDs, rebalance redox signaling, and restore immune function. Coupling these interventions to quantitative biomarkers of pigment oxidation, nitrosylation networks, and chemiexcitation activity may enable patient stratification and rational therapeutic sequencing, transforming melanin from a risk modifier into an actionable redox interface. <i>Antioxid. Redox Signal.</i> 44, 618-635.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"618-635"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12952693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen Sulfide as a Mediator of Protein Persulfidation and Motility Regulation in Mammalian Sperm.","authors":"Zuzana Pilsova, Aneta Pilsova, Natalie Zelenkova, Barbora Klusackova, Ondrej Simonik, Daniela Spevakova, Jessica Stekrova, Katerina Komrskova, Marketa Sedmikova, Pavla Postlerova","doi":"10.1177/15230864251410465","DOIUrl":"10.1177/15230864251410465","url":null,"abstract":"<p><strong>Aims: </strong>Hydrogen sulfide (H₂S) is a signaling molecule implicated in diverse physiological processes, yet its role in sperm function remains poorly understood. This study characterizes protein persulfidation, a post-translational modification mediated by H₂S in boar spermatozoa, tracks its distribution during sperm maturation, and assesses whether H₂S influences sperm motility during capacitation.</p><p><strong>Methods: </strong>Persulfidation was localized using fluorescent labeling and confirmed by Western blotting across epididymal and post-ejaculatory stages. LC-MS/MS identified persulfidated proteins, which were subsequently assigned to their biological roles. In functional assays, the H₂S biosynthesis inhibitor aminooxyacetic acid (AOAA) was applied at graded concentrations during sperm capacitation. These assays included computer-assisted sperm analysis (CASA) with k-means clustering, electrochemical measurement of H₂S, and flow cytometry to assess mitochondrial membrane potential.</p><p><strong>Results: </strong>Persulfidation was consistently detected in spermatozoa, predominantly in the midpiece, and persisted throughout maturation. Proteomic analysis revealed 36 persulfidated proteins, including regulators of motility, energy metabolism, and antioxidant defense. AOAA exposure induced time- and dose-dependent changes: early inhibition of H₂S synthesis reduced motility, whereas later recovery of H₂S levels correlated with better preservation of motility. Cluster analysis uncovered shifts in motile subpopulations, notably prolonged maintenance of hyperactivated-like sperm under AOAA treatment.</p><p><strong>Conclusion: </strong>This study provides the first comprehensive evidence that persulfidation is a functionally relevant modification in boar spermatozoa. H₂S appears to modulate motility during capacitation, either through persulfidation of proteins or via ion channels and other signaling pathways. These findings highlight H₂S signaling as a novel regulatory axis in male reproduction and suggest new avenues for fertility research. <i>Antioxid. Redox Signal.</i> 44, 572-598.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"572-598"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028184","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 Dysfunction in Renal Aging: A Vicious Cycle Driving Kidney Disease Progression.","authors":"Wenpei Yu, Qing Ouyang, Weicen Liu, Lu Jia, Bin Wang","doi":"10.1177/15230864251410936","DOIUrl":"10.1177/15230864251410936","url":null,"abstract":"<p><strong>Significance: </strong>The aging of the global population is linked to an increase in age-related diseases. The kidneys undergo both structural and functional declines with age, and aging is a significant risk factor for kidney diseases. Mitochondrial dysfunction is recognized as a crucial factor affecting kidney aging. Although the importance of disrupted mitochondrial homeostasis in renal aging has gained increasing attention, the associations and causal mechanisms have not been systematically summarized.</p><p><strong>Recent advances: </strong>Mitochondria are highly dynamic organelles that operate in various functions, including cell metabolism, redox regulation, cell division, and cell death, and are closely associated with both cell senescence and kidney diseases. Furthermore, aging is also associated with mitochondrial redox dysfunction, abnormal calcium homeostasis, impaired quality control (QC), and increased mitochondrial DNA (mtDNA) leakages. Mitochondrial dysfunction and cellular senescence may sustain a vicious cycle in renal injury. Several types of drugs show promising potential in alleviating renal injury by modulating mitochondria-related aging phenotypes.</p><p><strong>Critical issues: </strong>Dysregulated redox status, mitochondrial metabolic reprogramming, mtDNA abnormalities, impaired mitochondrial QC, and mitochondrial calcium overload are the factors that establish a self-perpetuating vicious cycle that promotes renal aging. In addition, the roles of mitochondria-associated senescence in both acute kidney injury and chronic kidney disease are examined and summarized, with potential differences and promising interventions targeting mitochondrial dysfunction and cell senescence also highlighted.</p><p><strong>Future directions: </strong>Clinically available interventions specifically aimed at addressing mitochondrial aging remain underdeveloped and require further clinical trials. Future research should also focus on creating drugs that can precisely target mitochondrial senescence to prevent the progression of age-related kidney diseases. <i>Antioxid. Redox Signal.</i> 44, 464-487.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":"44 10-12","pages":"464-487"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525695","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":"Hydrogen Attenuates Oxidative Damage via NRF2-Mediated Mitophagy after Subarachnoid Hemorrhage.","authors":"Jiatong Zhang, Yan Zhou, Xiaolong Zhu, Zheng Peng, Qi Zhu, Pengfei Ding, Mingzhe Ning, Qing-Rong Zhang, Zong Zhuang","doi":"10.1177/15230864251410952","DOIUrl":"10.1177/15230864251410952","url":null,"abstract":"<p><strong>Aims: </strong>Mitochondrial dysfunction is recognized as a central pathological mechanism in subarachnoid hemorrhage (SAH). This study aimed to investigate whether mitophagy serves as a key mechanism by which hydrogen (H₂) exerts its antioxidative effects following SAH.</p><p><strong>Results: </strong>Using <i>in vivo</i> (mouse SAH model) and <i>in vitro</i> (HT22 cell SAH model) approaches, we demonstrated that H₂ inhalation significantly improved neurological function and alleviated oxidative stress and apoptosis. Mechanistically, H₂ maintained mitochondrial membrane potential and functional integrity by enhancing phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. RNA sequencing and functional assays identified nuclear factor erythroid 2-related factor 2 (NRF2) as the key upstream target. H₂ promoted NRF2 nuclear translocation and activated the antioxidant pathway. Dual-luciferase reporter assays further confirmed that NRF2 directly binds to and activates the PINK1 promoter. Pharmacological inhibition of NRF2 (ML385) or mitophagy (Mdivi-1) abolished the protective effects of H₂, confirming that the NRF2-PINK1/Parkin axis is central to the effect of H₂.</p><p><strong>Innovation: </strong>The present study clearly establishes the NRF2-PINK1/Parkin axis as a key mechanism underlying the neuroprotective effect of H₂ in SAH. This study connects mitochondrial quality control with endogenous antioxidant systems, suggesting H₂ administration as a potential mitochondrion-targeted clinical intervention.</p><p><strong>Conclusion: </strong>The NRF2-PINK1/Parkin axis is a novel and key mechanism underlying the neuroprotective effect of H₂ in SAH. This finding advances our understanding beyond general antioxidant theories by demonstrating a specific, multistep molecular cascade. H₂ administration is a potential mitochondrion-targeted intervention with strong implications for clinical translation in SAH patients. <i>Antioxid. Redox Signal.</i> 44, 443-463.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"443-463"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861872","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":"Activation of Mitophagy by Kinetin Mitigates Coal-Silica Mixed Dust-Induced Pulmonary Fibrosis <i>via</i> Modulating Macrophage Mitochondrial Function in Mice.","authors":"Meiyu Chang, Qiang Zhou, Yi Guan, Yingzheng Zhao, Shuhan Guo, Qiufang Qu, Le Liu, Zhiheng Li, Xiangwei Zhao, Hong Cao, Sanqiao Yao","doi":"10.1177/15230864251411565","DOIUrl":"10.1177/15230864251411565","url":null,"abstract":"<p><strong>Aims: </strong>Coal workers' pneumoconiosis (CWP) is an occupational lung disease caused by the inhalation of coal dust. A key underlying pathogenic mechanism is driven by mitochondrial dysfunction and excessive reactive oxygen species (ROS), which trigger macrophage inflammation and cell death. Damaged mitochondria are selectively degraded <i>via</i> mitophagy, a process essential for maintaining mitochondrial homeostasis and promoting cell survival. However, the role of mitophagy dysregulation in dust-induced mitochondrial dysfunction and the underlying treatment with kinetin remain unclear. This study aimed to explore the role of PINK1/Parkin-mediated mitophagy in coal-silica mixed dust (CSD)-induced mitochondrial damage and to investigate the therapeutic potential of kinetin in targeting this pathway.</p><p><strong>Results: </strong>In this study, we compared the effects of CSD exposure and kinetin treatment on mitophagy, mitochondrial function, inflammation, and pulmonary fibrosis. We found that CSD exposure triggered ROS accumulation, mitochondrial membrane potential collapse, and impaired oxidative phosphorylation, leading to reduced adenosine triphosphate synthesis. Mechanistically, CSD suppressed PINK1/Parkin signaling and diminished LC3B mitochondrial recruitment, resulting in defective mitophagy. Notably, kinetin treatment and PINK1 overexpression restored PINK1/Parkin activation and LC3II-dependent mitophagy, alleviated mitochondrial dysfunction, and suppressed subsequent macrophage inflammation and pulmonary fibrosis. Genetic knockdown of PINK1 abolished the protective effects of kinetin, confirming a PINK1-dependent mechanism.</p><p><strong>Innovation: </strong>Our results revealed that kinetin is a PINK1-dependent mitophagy activator, positioning it as a promising therapeutic candidate for CWP by targeting mitochondrial integrity.</p><p><strong>Conclusion: </strong>Kinetin exerts its antifibrotic effects on CWP by promoting PINK1-mediated mitophagy, improving mitochondrial function, and alleviating macrophage inflammation. <i>Antioxid. Redox Signal.</i> 44, 528-549.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":"44 10-12","pages":"528-549"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525731","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 Retinoic Acid Receptor-Related Orphan Receptor α to Prevent Cataracts: A New Pathway Through Nerve Growth Factor Activation.","authors":"Zhenyu Wang, Jinda Wang, Xuemin Li, Yu Wan, Jing Tao","doi":"10.1177/15230864261416452","DOIUrl":"10.1177/15230864261416452","url":null,"abstract":"<p><strong>Aims: </strong>Cataracts are the leading cause of blindness worldwide, and the mechanism underlying cataract formation is linked to the oxidative damage and the apoptosis of lens epithelial cells. Retinoic acid Receptor-related orphan receptor α (RORα), a transcription factor, prevents oxidative stress and cell apoptosis. RORα is decreased in the lens from patients with cataract, but it remains unclear whether decreases in RORα are attributed to cataract formation.</p><p><strong>Results: </strong>Here, rat models of selenite-induced cataracts were used for <i>in vivo</i> experiments. <i>In vitro</i>, human lens epithelial cells (SRA01-04) were treated with selenite. RORα was downregulated in the lens from rat models of selenite-induced cataracts. The RORα agonist SR1078 significantly mitigated the degree of lens opacity. SR1078 reduced oxidative stress, cell apoptosis, and mitochondrial dysfunction and promoted the peroxisome proliferative activated receptor gamma coactivator (PGC-1α) and the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 pathways in the lens from rat models of selenite-induced cataracts and lens epithelial cells upon selenite stimulation. RORα overexpression showed a similar protective effect on lens epithelial cells <i>in vitro</i>. Nerve growth factor (NGF) expression was up-regulated by RORα overexpression. Although RORα overexpression prevented selenite-induced damage to lens epithelial cells, the damage recurred following NGF knockdown.</p><p><strong>Conclusion: </strong>RORα protects against selenite-induced oxidative stress and cellular apoptosis. In the context of cataractogenesis, NGF is newly identified as a transcriptional target of RORα, and its reduction is related to mitochondrial dysfunction in lens epithelial cells. Our study highlights the translational potential of RORα activation as a nonsurgical cataract intervention. <i>Antioxid. Redox Signal.</i> 44, 599-617.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"599-617"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146059010","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 TRIM31 to Boost Ferroptosis: A Promising Approach for Esophageal Cancer Therapy.","authors":"Ze Wang, Kejie Chang, Ke Zhang, Pei Wang, Guangjian Bai, Zhenhua Wang, Jian Xiao, Xin Tong, Jun Zhao","doi":"10.1177/15230864251411564","DOIUrl":"10.1177/15230864251411564","url":null,"abstract":"<p><strong>Aims: </strong>Esophageal squamous cell carcinoma (ESCC) is among the most lethal malignancies worldwide, with a five-year survival rate below 20%. Ferroptosis-a regulated form of cell death driven by iron-dependent lipid peroxidation-has emerged as a promising therapeutic strategy, yet its regulation in ESCC remains poorly understood. We investigated the role of tripartite motif-containing 31 (TRIM31), an E3 ubiquitin ligase, in ESCC progression and ferroptosis.</p><p><strong>Results: </strong>TRIM31 expression was significantly elevated in ESCC tissues compared with normal esophageal tissues (The Cancer Genome Atlas and Genotype-Tissue Expression datasets; <i>p</i> < 0.001) and correlated with advanced Tumor, Node, and Metastasis (TNM) stage (<i>p</i> = 0.004), lymph node metastasis (<i>p</i> = 0.024), and poor overall survival (<i>p</i> = 0.0027). Functional assays revealed that TRIM31 knockdown reduced ESCC cell proliferation, impaired colony formation, and suppressed migration (<i>p</i> < 0.01). <i>In vivo</i>, TRIM31 silencing decreased xenograft tumor volume by over 70% and Ki-67 expression by 73%. Mechanistically, TRIM31 directly interacted with VDAC1 <i>via</i> its coiled-coil domain, promoting VDAC1 ubiquitination and proteasomal degradation. This interaction inhibited ferroptosis, as evidenced by increased lipid reactive oxygen species, elevated intracellular Fe²⁺ levels, and mitochondrial damage upon TRIM31 knockdown. Conversely, TRIM31 overexpression attenuated ferroptosis induced by RSL3. We further identified hepatocyte nuclear factor 4 alpha as a transcriptional activator of TRIM31, binding to its promoter region. Importantly, TRIM31 knockdown synergized with the ferroptosis inducer imidazole ketone erastin, achieving a 90% reduction in tumor growth without significant toxicity.</p><p><strong>Conclusion: </strong>TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis. Targeting TRIM31 enhances ferroptosis-based therapy and represents a novel, clinically actionable strategy for ESCC treatment. <i>Antioxid. Redox Signal.</i> 44, 550-571.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":"44 10-12","pages":"550-571"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525705","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":"Exercise in a Pill: Emerging Therapeutics for Age-Related Orthopedic Diseases.","authors":"Jiayi Luo, Xin Meng, Juanjuan Han, Hui Kong, Xiaodong Wang, Xin-An Zhang","doi":"10.1177/15230864251411560","DOIUrl":"10.1177/15230864251411560","url":null,"abstract":"<p><strong>Significance: </strong>The global aging population has led to an increasing burden of age-related orthopedic diseases, seriously imposing social and economic pressures. Although exercise has been proven to have a protective effect on the musculoskeletal system, diseases themselves often restrict patients from engaging in physical activity. Exercise mimetics, as a pharmacological intervention that can simulate or enhance the benefits of exercise, offer new treatment options for such patients.</p><p><strong>Recent advances: </strong>Exercise mimetics modulate oxidative stress, inflammatory responses, and apoptosis to enhance bone mineral density, improve trabecular microarchitecture, facilitate cartilage nourishment, and augment muscular strength and endurance. They have shown promising therapeutic potential in disease models such as osteoarthritis, intervertebral disc degeneration, osteoporosis, and sarcopenia. Some compounds such as metformin and resveratrol have been used in clinical research.</p><p><strong>Critical issues: </strong>This review summarizes the mechanism of action and the latest research progress on exercise mimetics in degenerative orthopedic diseases and analyzes the current translational challenges and limitations in the research.</p><p><strong>Future directions: </strong>Future research should further clarify the tissue-specific effects of exercise mimetics, the long-term safety of their use, and individual differences in their therapeutic efficacy. Meanwhile, developing targeted delivery systems, optimizing bioavailability, and promoting more rigorously designed clinical studies will help achieve wide application of exercise mimetics in the treatment of orthopedic diseases. <i>Antioxid. Redox Signal.</i> 44, 488-527.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":"44 10-12","pages":"488-527"},"PeriodicalIF":6.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525699","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":"THRA Orchestrates Myocardial Protection Against Hypothyroidism-Induced Ferroptosis <i>via</i> the GATA4-GPX4 Transcriptional Cascade.","authors":"Zhang Runfang, Xianen Fa","doi":"10.1177/15230864251399166","DOIUrl":"10.1177/15230864251399166","url":null,"abstract":"<p><strong>Aims: </strong>Hypothyroidism frequently causes myocardial injury, but the role of <i>thyroid hormone receptor alpha</i> (<i>THRA</i>) remains unclear. This study investigated the function and mechanism of <i>THRA</i> in hypothyroidism-associated cardiac damage.</p><p><strong>Methods: </strong>A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and <i>THRA</i>-knockout (KO) groups with or without thyroxine (T4) treatment. Systemic parameters, cardiac injury, histopathology, and molecular pathways were analyzed using enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, quantitative polymerase chain reaction, RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays.</p><p><strong>Results: </strong>PTU-induced hypothyroidism significantly reduced body weight, impaired cardiac function, and dysregulated thyroid hormones. <i>THRA</i> KO exacerbated these effects and completely abolished the therapeutic response to T4. Crucially, group KO-M markedly elevated markers of ferroptosis, including iron overload, malondialdehyde, and reactive oxygen species, while suppressing the reduced-to-oxidized glutathione ratio (GSH/GSSG) and key antiferroptotic proteins like <i>glutathione peroxidase 4</i> (<i>GPX4</i>), compared with group M. Mechanistically, we identified <i>GATA binding protein 4</i> (<i>GATA4</i>) as an upstream transcriptional activator of <i>THRA</i>. Furthermore, <i>THRA</i> itself directly bound to the <i>GPX4</i> promoter and transactivated its expression. This <i>GATA4</i>-<i>THRA</i>-<i>GPX4</i> axis was essential for cardioprotection, alongside modulation of the <i>phosphoinositide 3-kinase</i>/<i>protein kinase B</i> signaling pathway.</p><p><strong>Conclusion: </strong>This study defines the <i>GATA4</i>-<i>THRA</i>-<i>GPX4</i> transcriptional axis as a crucial mechanism that protects the heart from hypothyroidism-driven ferroptosis, uncovering a previously unrecognized transcriptional axis that is crucial for cardioprotection during hypothyroidism. <i>Antioxid. Redox Signal.</i> 44, 236-250.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"236-250"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145628121","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":"Zinc Protoporphyrin Functions as a Ferroptosis Inducer to Activate Heme-BACH Axis and Potently Suppress IDH1-Mutant Gliomas.","authors":"Ying Yang, Yating Nie, Ruolin Wu, Ruili Han, Yuanlin Zhao, Risheng Yang, Yuan Yuan, Xing Gao, Huangtao Chen, Feng Zhang, Liying Zhang, Lijun Zhang, Xiangmei Cao, Yingmei Wang, Peizhen Hu, Jing Li, Zengshan Li, Zhe Wang, Jing Ye, Yu Gu","doi":"10.1177/15230864251394709","DOIUrl":"10.1177/15230864251394709","url":null,"abstract":"<p><strong>Aims: </strong>Ferroptosis shows promise as a cancer treatment due to lipid hydroperoxide accumulation in an iron-dependent manner. Isocitrate dehydrogenase 1 (IDH1) mutation is common in gliomas and D-2-hydroxyglutarate (D-2HG) sensitizes cancer cells to ferroptosis. However, the regulation of ferroptosis in IDH1 mutant gliomas remains unclear. We hypothesize that IDH1 mutations induce glioma ferroptosis by regulating iron metabolism and antioxidant systems through the heme-BACH axis.</p><p><strong>Results: </strong>IDH1 mutation induces ferroptosis in astrocytes and glioma cells demonstrated by growth inhibition, mitochondrial damage, and lipid peroxidation. In IDH1-mutant gliomas, both Fe²⁺ and reactive oxygen species accumulate due to impaired heme biosynthesis and thus BACH activation-dependent transcriptional repression of iron homeostasis and antioxidant response-related genes. The heme analogs zinc and tin protoporphyrin IX (ZnPP and SnPP) function as competitive inhibitors to reduce heme-dependent degradation of BACH and to exacerbate ferroptosis, especially for IDH1 mutants at extremely low concentrations. Primary mouse astrocytes and human glioma cell lines were used to determine the effect of IDH1 mutation on ferroptosis, while orthotopic xenograft models were used to evaluate heme analog efficacy. The drug affinity responsive target stability assay was used to determine the interaction between heme and its analog and BACH.</p><p><strong>Innovation and conclusions: </strong>We discover that IDH1 mutation induces ferroptosis by activating the heme-BACH axis. ZnPP, previously believed to function exclusively as a heme oxygenase-1 inhibitor, can competitively bind to BACH to exacerbate ferroptosis and potently suppress IDH1-mutant gliomas. This study reveals a novel metabolic mechanism for inducing ferroptosis and provides a potential therapeutic target for IDH-mutant gliomas. Paraffin-embedded human glioma samples were collected from Xijing Hospital, the First Affiliated Hospital of the Fourth Military Medical University (China) (project number: KY20233192-1). <i>Antioxid. Redox Signal.</i> 44, 145-163.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"145-163"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817496","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}