Significance: Bronchopulmonary dysplasia (BPD) remains a major chronic lung disease of prematurity and an important cause of long-term respiratory morbidity in preterm infants. As survival of extremely preterm infants has improved, the clinical burden of BPD has remained substantial. Redox dysregulation, characterized by an imbalance among oxidant exposure, antioxidant capacity, and adaptive signaling responses, represents a central pathogenic mechanism in BPD and contributes to impaired alveolar and vascular development, inflammatory amplification, and defective lung repair.Recent Advances: Current neonatal management strategies, including optimized respiratory support, careful oxygen targeting, nutritional support, caffeine therapy, and selective corticosteroid use, may reduce oxidant burden or modulate redox-sensitive injury pathways. In parallel, antioxidant-related interventions-including vitamins, trace elements, glutathione-related therapies, natural products, and pharmacological agents-have demonstrated biological plausibility.Critical Issues: Current interventions do not consistently correct the underlying redox imbalance of the immature lung. The clinical translation of antioxidant-related therapies remains limited and highly dependent on the level of evidence, intervention timing, and biological context. This review summarizes the role of redox dysregulation in the pathogenesis of BPD and critically examines the clinical and preclinical evidence for redox-related interventions.Future Directions: Emerging priorities include biomarker-guided therapy, omics-informed risk stratification, targeted pulmonary delivery, precision nutritional strategies, and integrated multimodal approaches. Future progress in BPD prevention and treatment will likely depend on integrating redox-informed approaches with established neonatal care, targeted interventions, and rigorous long-term clinical evaluation. Antioxid. Redox Signal. 00, 000-000.
AIMS:Persistent inflammation is recognized as a major driver of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet upstream macrophage-activation signals remain incompletely understood. Here, we investigated whether the urokinase receptor (uPAR), traditionally linked to matrix remodeling, functions instead as an inflammatory signaling hub that links kidney injury to chronic fibrotic remodeling. RESULTS:In a unilateral renal ischemia-reperfusion injury model, uPAR was induced during the fibrotic phase of postischemic kidney injury. Functional enhancement- and loss-of-function approaches revealed a striking dichotomy: exogenous urokinase (uPA) aggravated renal dysfunction, inflammation, oxidative stress, and fibrosis, whereas uPAR deletion was protective. Mechanistically, uPA/uPAR signaling amplified macrophage inflammatory responses, enhancing M1 polarization, pro-inflammatory cytokine production, reactive oxygen species generation, and NF-κB activation. Molecular docking, mutational modeling, and co-immunoprecipitation analyses revealed a previously underappreciated association between activated uPAR and toll-like receptor 4 (TLR4)-containing complexes. This interaction enhanced myeloid differentiation primary response gene 88-dependent NF-κB signaling and potentiated macrophage inflammatory amplification rather than initiating inflammation independently. NF-κB blockade abolished the pro-inflammatory effects of uPA/uPAR signaling, establishing the functional importance of this pathway. INNOVATION:We demonstrate that uPA-activated uPAR engages TLR4-associated signaling to intensify macrophage-driven inflammation, oxidative stress, and fibrotic remodeling. These findings redefine uPAR as a molecular switch governing maladaptive kidney repair and identify the uPA/uPAR-TLR4 signaling interface as a promising therapeutic target. CONCLUSION:Our findings suggest that the uPA/uPAR-TLR4 axis is involved in regulating the progression from AKI to fibrosis. Targeting this signaling node may represent a novel strategy to interrupt maladaptive repair and prevent CKD following AKI. Antioxid. Redox Signal. 00, 000-000.
AIMS:Intestinal mucosal barrier injury is a major consequence of intestinal ischemia-reperfusion (II/R) and contributes to poor clinical outcomes. While mitophagy sustains mitochondrial homeostasis, how impaired autophagic flux disrupts intestinal barrier function remains unclear. We investigated the role of the deubiquitinase ubiquitin-specific protease 26 (USP26) and its downstream target syntaxin 17 (STX17) in regulating mitophagy and intestinal barrier repair. METHODS:II/R mouse models and oxygen-glucose deprivation/reperfusion (OGD/R)-treated Caco-2 cells were used to evaluate intestinal barrier integrity. Functional manipulation, autophagy blockade, Co-IP, ubiquitination assays, Seahorse metabolic detection, and in vivo rescue assays were performed to dissect the USP26-STX17 regulatory axis. RESULTS:USP26 was markedly downregulated in II/R intestinal tissues and OGD/R Caco-2 cells, coinciding with impaired autophagy, mitochondrial dysfunction, and intestinal barrier disruption. USP26 overexpression preserved intestinal architecture, reduced permeability and apoptosis, and restored expression of the tight-junction proteins. Functionally, USP26 enhanced autophagic flux and mitophagy, as evidenced by increased LC3-II/LC3-I ratios, reduced p62 accumulation, elevated PINK1/Parkin signaling, improved adenosine triphosphate production, restored mitochondrial membrane potential, and normalized cellular bioenergetics; autophagy inhibition attenuated these protective phenotypes. Mechanistically, USP26 bound STX17 and stabilized it via deubiquitination. STX17 knockdown impaired autophagosome-lysosome fusion and largely abolished USP26-mediated mitochondrial and intestinal barrier protection in vitro and in vivo. CONCLUSIONS:This study identifies the USP26-STX17 axis as a previously unrecognized regulator of autophagosome-lysosome fusion and mitophagy in II/R injury. By restoring mitochondrial quality control and epithelial barrier integrity, USP26 emerges as a promising therapeutic target for the prevention and treatment of gut barrier dysfunction associated with critical illness. Antioxid. Redox Signal. 00, 000-000.
BACKGROUND:Bronchial asthma associated with acute or chronic lung injury has emerged as a significant public health concern due to environmental chemical pollution, particularly following the widespread application of sodium hypochlorite (NaClO) disinfectant during the COVID-19 pandemic. Captopril, an antihypertensive agent, has been shown to alleviate symptoms; understanding the mechanism of captopril-mediated protection could facilitate the development of more effective therapeutic strategies. BEAS-2B is a line of immortalized human bronchial epithelial cells, widely used as an in vitro model to investigate pulmonary toxicology. This study investigated the mechanism by which captopril protects the lung and BEAS-2B cells against NaClO-induced lung injury. METHODS:Lung injury was induced in mice by NaClO nebulization and in BEAS-2B cells by NaClO treatment. The role of captopril was investigated via physiological monitoring, angiotensin-converting enzyme (ACE) knockdown, and multiomic biochemical analyses focusing on reactive oxygen species (ROS) generation, mitochondrial integrity, and apoptotic/autophagic signaling pathways. RESULTS:Captopril significantly inhibited NaClO-induced apoptosis and suppressed intracellular ROS, reducing oxidative products such as malondialdehyde (MDA) and oxidized glutathione, while simultaneously upregulating the expression of antioxidant enzymes. Furthermore, captopril reduced pro-inflammatory cytokine levels in BEAS-2B cells. It also reduced excessive mitochondrial ROS production and mitigated the NaClO-induced elevation of mitochondrial membrane potential. Notably, the protective effects of captopril were maintained in ACE gene-knockdown BEAS-2B cells, suggesting a potential ACE-independent mechanism. Captopril markedly alleviated NaClO-induced pulmonary injury, specifically improving NaClO-triggered lung dysfunction in mice. Mechanistically, captopril inhibited NaClO-induced apoptosis by upregulating B cell lymphoma 2 (Bcl-2) and downregulating FAS, cleaved caspase 3, and Bcl-2-associated X protein levels. This was linked to captopril suppressing tissue ROS generation, decreasing MDA content, elevating reduced glutathione, and enhancing the expression of antioxidant enzymes. Captopril also alleviated pulmonary and systemic inflammation and regulated autophagy-related proteins, thereby alleviating NaClO-induced dysregulation of autophagy. CONCLUSION:Together, these findings indicate that captopril holds promise as a potent antioxidant agent to alleviate NaClO-induced lung injury. Antioxid. Redox Signal. 00, 000-000.
Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.
SIGNIFICANCE: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. RECENT ADVANCES: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. CRITICAL ISSUES: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. FUTURE DIRECTIONS: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. Antioxid. Redox Signal. 00, 000-000.
Copper–zinc superoxide dismutase (CuZnSOD) is an antioxidant enzyme that protects against oxidative damage. Oxidative stress plays a well-established role in the pathogenesis of rheumatoid arthritis (RA), being associated with elevated production of reactive oxygen and nitrogen species, along with enhanced lipid peroxidation, protein oxidation, and DNA damage. This study investigated the association between serum CuZnSOD levels and disease-related features in patients with RA, with a particular focus on cardiovascular (CV) comorbidity. A total of 150 patients with RA were enrolled in this cross-sectional study. After multivariable adjustment, CuZnSOD concentrations were not associated with most disease characteristics or activity measures, except for rheumatoid factor positivity, which was independently linked to higher CuZnSOD levels. Among CV parameters, CuZnSOD showed a positive correlation with the Systematic Coronary Risk Evaluation-2 CV risk calculator, both as a continuous and categorical variable, with the highest values observed in patients classified as very high risk. Besides, insulin levels were inversely related to CuZnSOD after adjustment. By combining multivariable analysis with broad phenotypic characterization, these findings support the hypothesis that CuZnSOD may reflect CV risk-related biology rather than disease activity in patients with RA. In conclusion, CuZnSOD serum levels in RA are linked to CV risk but not to joint disease activity. Antioxid. Redox Signal. 00, 000–000.
SIGNIFICANCE: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 via spatially compartmentalized NOX signaling. RECENT ADVANCES: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. CRITICAL ISSUES: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 in vitro 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. FUTURE DIRECTIONS: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. Antioxid. Redox Signal. 00, 000-000.
AIMS:Senile vaginitis is a common clinical condition with limited treatment options. Estrogen deficiency leads to atrophy of the vaginal walls and thinning of the mucosa. It is noteworthy that although vaginal atrophy is an almost universal consequence of menopause, many postmenopausal women do not develop genitourinary symptoms. These observations collectively indicate that estrogen-independent pathogenic mechanisms are involved. In our preliminary study, through metabolomic screening, we identified three functionally relevant metabolites, namely guggulsterone (GS), umbelliprenin, and inosinic acid. This study seeks to elucidate the pathogenic mechanism of GS in senile vaginitis and to unveil novel therapeutic avenues for this condition. RESULTS:Cellular and animal experiments confirm that GS elevates intracellular ferrous iron (Fe2+), malondialdehyde, and reactive oxygen species levels in vaginal epithelial cells, thereby inducing ferroptosis and upregulating the expression of inflammatory factors in vaginal tissues. Consequently, these processes compromise vaginal mucosal integrity, thereby exacerbating epithelial atrophy and the progression of inflammation. Treatment with the ferroptosis inhibitor ferrostatin-1 partially reversed the accumulation of Fe2+, lipid peroxides, and cellular oxidative stress. By utilizing a combination of lipidomic mass spectrometry, molecular docking, and surface plasmon resonance, it was collectively demonstrated that GS directly binds to heme oxygenase 1 (HMOX1). Utilizing VK2/E6E7 cell models with lentivirus-mediated HMOX1 knockdown and overexpression, this study demonstrates that GS might contribute to ferroptosis in vaginal epithelial cells by upregulating HMOX1 expression. Notably, treatment with MG132 potentiated the GS-induced upregulation of HMOX1, whereas the autophagy-lysosome inhibitor bafilomycin A1 had no significant effect. These findings suggest that GS may upregulate HMOX1 levels by inhibiting its degradation through the proteasome pathway. INNOVATION AND CONCLUSION:Collectively, these findings establish GS as a critical regulator of vaginal epithelial cell ferroptosis through HMOX1 targeting, revealing new therapeutic avenues for senile vaginitis. Antioxid. Redox Signal. 00, 000-000.
AIMS:Obstructive sleep apnea (OSA)-associated chronic intermittent hypoxia (CIH) induces lung injury, partly through ferroptosis. Although resveratrol (Res) exhibits antioxidant activity, its mechanism in mitigating ferroptosis under CIH remains unclear. This study aimed to determine whether Res attenuates CIH-induced lung injury by suppressing ferroptosis and to elucidate the role of Sirtuin 1 (SIRT1)-dependent modulation of the early growth response factor 1 (EGR1)/glutaminase 2 (GLS2) axis. RESULTS:CIH models were established using Sprague-Dawley rats and human bronchial epithelial BEAS-2B cells, treated with optimal doses of Res. In vivo, Res treatment significantly attenuated alveolar structural damage, enhanced glutathione (GSH) biosynthesis, and upregulated the expression of glutathione peroxidase 4 (GPX4). In vitro, Res reversed CIH-induced ferroptotic phenotypes and restored mitochondrial morphological integrity in BEAS-2B cells. Mechanistically, Res activated SIRT1. Integrated analysis of RNA sequencing and the FerrDb database identified EGR1 as a pivotal downstream effector of SIRT1-mediated ferroptosis regulation. Rescue experiments demonstrated that EGR1 knockdown abrogated the anti-ferroptotic effects conferred by both Res treatment and SIRT1 overexpression, indicating that SIRT1 suppresses ferroptosis via EGR1 upregulation. Furthermore, bioinformatics prediction and dual-luciferase reporter assays confirmed that EGR1 directly binds to and transcriptionally activates the promoter of GLS2. Consequently, GLS2 knockdown attenuated the protective effects of Res, whereas GLS2 overexpression augmented GSH production and suppressed ferroptosis. INNOVATION AND CONCLUSION:Res alleviates CIH-induced lung injury by inhibiting ferroptosis via SIRT1-dependent modulation of the EGR1/GLS2 axis. These findings reveal a novel mechanism in OSA pathophysiology and highlight Res as a promising therapeutic candidate for CIH-induced lung injury. Antioxid. Redox Signal. 00, 000-000.
BACKGROUND: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. METHODS: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). RESULTS:Ischemia-reperfusion triggered hyperactivated autophagy, which promoted ferroptosis by selectively targeting ACSL3 for degradation via 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. CONCLUSION: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. Antioxid. Redox Signal. 00, 000-000.
AIMS: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 via the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity. RESULTS: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 in vitro and in vivo. Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes (Sqstm1, Fundc1, Bnip3) 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 CD150high HSCs, a hallmark of aging. CONCLUSION:Targeted mitophagy restoration via 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. Antioxid. Redox Signal. 00, 000-000.
AIMS:Selenium-binding protein 1 (SELENBP1) correlates positively with the prognosis of patients with colitis and colon cancer. SELENBP1-deficient dendritic cells (DCs) promote regulatory T cell differentiation and exert direct immunomodulatory functions. This study aimed to investigate whether SELENBP1-deficient DCs mediate antitumor immune function by affecting CD8+ T cell activation or exhaustion. RESULTS:Our findings revealed that SELENBP1 deficiency in mice accelerates colon cancer progression, characterized by reduced numbers of activated DCs and cytotoxic CD8+ T cells, increased intratumoral exhaustion-related factors, and impaired CD8+ T cell tumor-killing capacity. Adoptive-transfer experiments showed that SELENBP1 deficiency impairs DC antitumor activity, which may be associated with decreased intratumoral DCs, reduced cytotoxic CD8+ T cells, and increased dysfunctional T cell phenotypes. Moreover, in vitro cell experiments showed that the phosphatidylinositol 3-kinase/protein kinase B and hypoxia-inducible factor-1-alpha pathways are involved in DC migration as well as DC-mediated phenotypic dysfunction of CD8+ T cells. In addition, SELENBP1 expression in conventional DCs correlated positively with cytotoxic CD8+ T cells. INNOVATION:This study is the first to investigate the antitumor immune function of SELENBP1 in DCs. CONCLUSION:In vitro experiments showed that SELENBP1 deficiency impairs DC migration and maturation, resulting in decreased cytotoxic CD8+ T cells and increased dysfunctional T cell phenotypes. This phenomenon may underlie the accelerated colon tumor progression observed upon global SELENBP1 ablation or adoptive transfer of SELENBP1-deficient DCs. In brief, SELENBP1 deficiency impairs DC-mediated antitumor immune function. Antioxid. Redox Signal. 00, 000-000.
AIMS:Radiation-induced intestinal injury (RIII) severely compromises the quality of life in patients undergoing abdominal/pelvic radiotherapy and may necessitate treatment discontinuation. To date, there is no approved agent for the prevention or treatment of RIII. This study aims to clarify the protective effects of mannose on RIII and elucidate its mechanisms of action, in order to identify new safe and effective therapeutic agents and potential therapeutic targets for the prevention and treatment of RIII. RESULTS:Here, we report that intraperitoneal administration of mannose, a natural bioactive monosaccharide, at 24, 12, and 2 h prior to lethal irradiation increased the survival rate of mice from 0% to 50%. Specifically, mannose pretreatment significantly blocked crypt cell apoptosis, preserved epithelial barrier integrity, attenuated intestinal inflammation, and enhanced crypt regeneration. Additionally, mannose treatment enhanced the survival of intestinal stem cells both in vitro and in vivo following radiation exposure. We further confirmed that mannose maintains mitochondrial homeostasis and alleviates cellular oxidative stress. Moreover, mannose facilitated the repair of DNA double-strand breaks, thereby inhibiting aberrant mitosis after radiation exposure. Additionally, preliminary evidence indicates that mannose does not affect the radiosensitivity of colorectal tumor cells or azoxymethane/dextran sodium sulfate-induced colorectal tumors in mice.Conclusion and Innovation:Given its low toxicity and wide availability, our findings suggest that mannose represents a promising protective strategy for RIII. Antioxid. Redox Signal. 00, 000-000.
SIGNIFICANCE: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. RECENT ADVANCES:We outline how upstream nucleic acid sensors, notably Z-DNA binding protein 1 (ZBP1) 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 Ca2+ 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 ZBP1-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. CRITICAL ISSUES: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. FUTURE DIRECTIONS:Future strategies should prioritize nanomedicine-enabled precision delivery, metabolic reprogramming, and time-sensitive intervention across the athero-myocardial axis. INNOVATION: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-based propagation mechanisms, and maps time-sensitive therapeutic windows across endothelial injury, plaque progression, reperfusion injury, and remodeling. Antioxid. Redox Signal. 45, 456-473.
AIMS: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 (FXN) 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). RESULTS: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. INNOVATION:These findings reveal variability in drug responses based on FRDA genetic profiles and position SF as a promising drug to address multiple pathological processes. CONCLUSION:Our preclinical data support SF as a strong FRDA drug candidate. Clinical evaluation is warranted to confirm its full therapeutic potential. Antioxid. Redox Signal. 00, 000-000.
BACKGROUND:Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear. METHODS:Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (Irg1) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms. KEY FINDINGS:Irg1 expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression. CONCLUSIONS:This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. Antioxid. Redox Signal. 45, 512-533.
AIM:The activation of microglia triggers an inflammatory response, which is frequently associated with an imbalance of iron metabolism. This study aimed to determine whether inflammation-associated iron dyshomeostasis contributes to impaired poststroke recovery and to explore the underlying mechanisms. RESULTS:Ferroportin 1 (FPN1) deficiency in neurons and glial cells delayed sensorimotor function recovery following cerebral ischemia. FPN1 deficiency was associated with aggravated neuronal injury, enhanced apoptosis- and necroptosis-associated signaling, impaired myelin- and synapse-related repair, and reduced dendritic spine density in the ischemic cortex. Histological analyses, including hematoxylin and eosin staining and Nissl staining, further supported more severe peri-infarct pathological damage in Fpn1Nestin-CKO mice. In addition, increased IgG extravasation indicated aggravated blood-brain barrier (BBB) disruption and secondary neurovascular injury after stroke. These pathological changes were accompanied by increased iron accumulation in the ischemic cortex and altered expression of iron metabolism-related molecules. Elevated inflammatory cytokine expression and increased hepcidin levels were associated with disrupted brain iron homeostasis in Fpn1Nestin-CKO mice. Inhibition of JAK-STAT signaling with AG490 reduced p-STAT3 and hepcidin levels and was associated with modulation of iron-related and repair-associated responses, with more pronounced effects observed in Fpn1-deficient mice. INNOVATION AND CONCLUSION:These findings highlight a close association between inflammatory signaling, BBB dysfunction, and iron dyshomeostasis during poststroke recovery. Our results suggest that delayed sensorimotor recovery in mice with neuronal and glial FPN1 deficiency may be linked to inflammation-associated BBB disruption and subsequent iron accumulation in the ischemic brain. Antioxid. Redox Signal. 45, 417-434.
AIMS:This study aimed to delineate a novel mechanistic axis linking hyperglycemia-driven glycolytic reprogramming to ferroptotic death in lens epithelial cells (LECs) and to determine its therapeutic significance in diabetic cataract (DC). Specifically, we sought to define the integration of metabolic, epigenetic (histone lactylation), and post-translational (fucosylation) pathways in DC pathogenesis. RESULTS:Under hyperglycemic conditions, LECs exhibited robust glycolytic activation and lactate accumulation. This metabolic shift drove selective histone H3K18 lactylation at the promoter of theTSTA3 gene, leading to its increased transcription. The upregulated TSTA3 protein then promoted the core fucosylation of the NF-κB p50 subunit, which facilitated its nuclear translocation. Inside the nucleus, p50 transcriptionally activatedNOX1, resulting in excessive reactive oxygen species (ROS) production and subsequent ferroptotic cell death. Critically, both pharmacological inhibition of glycolysis and genetic silencing ofTSTA3 effectively attenuated oxidative stress, restored redox balance, and ameliorated cataract severity in a diabetic rat model. INNOVATION:This work identifies a previously unrecognized pathogenic cascade-the glycolysis-histone lactylation-fucosylation-ferroptosis axis-that directly links metabolic flux to epigenetic and signaling control in DC. By positioning TSTA3 as a central, druggable node within this axis, our study redefines cataract pathogenesis beyond simple oxidative damage, integrating multiple layers of cellular regulation. CONCLUSION:The glycolysis-histone lactylation-TSTA3-fucosylation-NOX1-ferroptosis axis is a critical driver of LEC death in diabetic cataract. Targeting this newly defined pathway, particularly the TSTA3 node, offers novel opportunities for mechanism-based therapeutic interventions and biomarker development, with potential implications for other complications of metabolic disease. Antioxid. Redox Signal. 45, 474-490.
SIGNIFICANCE:Hydrogen sulfide (H2S), a vital gasotransmitter in liver physiology and pathology, is produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST). Although CSE and CBS have been extensively studied in liver diseases, the role of MPST has received less attention, despite its significant and complex regulatory functions in hepatic biology and metabolism. RECENT ADVANCES:The involvement of MPST in antioxidant processes, mitochondrial function, and protein persulfidation highlights its multifaceted role in various liver diseases, where it can act either as a protective factor or as a contributor to disease progression, primarily through H2S metabolism. Notably, MPST also participates in crosstalk between various organs, including adipose-liver, gut-liver, skeletal muscle-liver, and pancreas-liver interactions. We also summarize current genetic models and pharmacological modulators targeting MPST. This review highlights the importance of advancing our understanding of the MPST/H2S pathway to develop promising therapeutic strategies for liver diseases. CRITICAL ISSUES:Current research focuses mainly on changes in the expression of MPST in liver diseases, but its underlying mechanisms require further elucidation. The available genetic and pharmacological tools are still limited, underscoring the need for specific modulators and tissue- or cell-specific conditional MPST knockout or knock-in models to advance future investigations. FUTURE DIRECTIONS:Future research should focus on delineating stage-specific and cell type-dependent mechanisms of MPST in liver diseases, identifying upstream regulators, and elucidating detailed downstream molecular pathways mediating the effects of MPST. Ultimately, these efforts should aim to establish the clinical significance of MPST as a translational target. Antioxid. Redox Signal. 45, 491-511.
