Redox Biology最新文献

{"title":"Cathepsin S regulates ferroptosis sensitivity in hepatocellular carcinoma through the KEAP1-NRF2 signaling pathway.","authors":"Ru-Chen Xu,Jia-Lei Sun,Fu Wang,Hua-Hua Liu,Zhuo-Ran Qi,Xuan Shi,Xiang-Nan Yu,Tao-Tao Liu,Shu-Qiang Weng,Ling Dong,Xi-Zhong Shen,Ji-Min Zhu","doi":"10.1016/j.redox.2025.103815","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103815","url":null,"abstract":"Ferroptosis is a newly discovered iron-dependent programmed cell death characterized by excess lipid peroxidation. It is emerging as a promising target for tumor therapies. In the present study, we first identify Cathepsin S (CTSS) as a novel ferroptosis regulator. CTSS is upregulated in ferroptosis-resistant hepatocellular carcinoma (HCC) cells, and suppression of CTSS sensitizes HCC cells to ferroptosis. Mechanistically, ferroptosis stress induces CTSS maturation and promotes the autophagy-lysosomal degradation of Kelch-like ECH-associated protein 1 (KEAP1). This process blocks KEAP1-dependent, ubiquitination-mediated degradation of nuclear factor E2-related factor 2 (NRF). Consequently, the accumulated NRF2 translocates from the cytoplasm to the nucleus and drives the transcription of anti-ferroptosis genes. In vivo study reveals that CTSS depletion, achieved through either shRNA or the specific inhibitor LY3000328, in combination with a ferroptosis inducer, inhibits HCC tumor growth in orthotopic xenograft mouse models. In conclusion, the above data suggest that CTSS can potentiate ferroptosis in HCC cells and may be a therapeutic target to overcome ferroptosis resistance in HCC patients.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"23 1","pages":"103815"},"PeriodicalIF":11.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of eIF5A hypusination enhances antioxidant defense to prevent kidney Ischemia/Reperfusion injury.","authors":"Marc Cougnon,Sébastien Giraud,Maria Materozzi,Elisa Allart,Isabelle Rubera,Claire Mackowiak,Gisèle Jarretou,Nadège Boildieu,Virginie Ameteau,Estelle Lemarié,Hajar Ouahmi,Nicolas Melis,Mallorie Poet,Christophe Duranton,Luc Pellerin,Laurent Counillon,Marina Shkreli,Michel Tauc,Thierry Hauet,Didier F Pisani","doi":"10.1016/j.redox.2025.103814","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103814","url":null,"abstract":"Ischemia/reperfusion (I/R) refers to the interruption or reduction of blood flow followed by its sudden restoration, resulting in significant oxidative stress, particularly in the kidneys, which are highly oxygen-dependent and metabolically active. During I/R, excessive production of reactive oxygen species (ROS) is triggered by mitochondrial dysfunction and activation of oxidases. Cellular antioxidant defences which attempt to neutralise ROS can become overwhelmed, resulting in oxidative stress that damages macromolecules and ultimately impairs cell function and survival. In kidney transplantation, ROS-induced I/R injury contributes to delayed graft function and chronic graft loss. In this context, inhibition of eIF5A hypusination using the deoxyhypusine synthase inhibitor GC7 protects kidney against I/R injury, potentially by reducing oxidative stress. However, the exact mechanisms and dynamics of this antioxidant protection remain to be elucidated. Using a mouse model of renal I/R and equivalent in vitro cell model, we analyzed the concomitance between protection against oxidative stress due to GC7 treatment and recovery of renal function or cell survival. In addition, we analyzed proteome modulation due to GC7 treatment to unravel pathways involved in its protective effect, and we defined the impact of GC7 on ROS productions and on antioxidant defences. We demonstrated that GC7 protected against I/R-induced injury and anoxia/reoxygenation in both in vivo and in vitro models by conditioning the cells and organ to resist stress. From a mechanistic point of view, we showed that the protective effects of GC7 were largely attributed to the enhancement of antioxidant defences, mainly through sustained catalase activity, which was mandatory in kidney cells to survive in the face of ROS production. Overall, GC7 is a clinical candidate for reducing oxidative damage in kidney transplantation, particularly for organs from marginal donors. Its ability to reprogram redox and metabolic pathways early after treatment supports its use to improve graft survival and function.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"5 1","pages":"103814"},"PeriodicalIF":11.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOX-NOS crosstalk in the liver-brain axis: Novel insights for redox regulation and neurodegenerative diseases.","authors":"Sang-Seop Lee,Yung-Choon Yoo","doi":"10.1016/j.redox.2025.103807","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103807","url":null,"abstract":"The liver-brain axis is an emerging concept linking liver dysfunction and brain disease. Hepatic metabolic abnormalities induce systemic oxidative stress and endothelial dysfunction, which contribute to central nervous system (CNS) inflammation and neurodegeneration. Redox regulation plays a key role in the liver-brain axis, with NADPH oxidase (NOX) and nitric oxide synthase (NOS) being involved in the generation of various reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively, thereby inducing oxidative stress and disrupting the NADPH/NADP balance. Dysregulation of NOX-NOS cross-signaling not only amplifies oxidative stress, but also disrupts endothelial homeostasis and exacerbates neuroinflammation, leading to progressive neurodegeneration. For instance, reactive carbonyl species such as methylglyoxal (MGO) and acrolein can upregulate NOX isoforms and stimulate NLRP (NOD like receptor protein) inflammasomes activation, illustrating disease-relevant links between hepatic redox imbalance and CNS pathology. Mechanistically, superoxide (O2•-) generated by NOX readily reacts with nitric oxide (•NO) derived from NOS to form peroxynitrite (ONOO-), a highly reactive oxidant that exacerbates vascular and neuronal injury. Despite extensive research on NOX and NOS, their interactive contributions to redox imbalance and the progression of neurodegenerative diseases remain poorly understood. In this review, we introduce the NOX-NOS axis as a key regulator of the liver-brain axis, and highlight the roles of NOX and NOS in linking hepatic metabolic dysfunction to central nervous system pathology through intermediary metabolites in the exacerbation of neuroinflammation and oxidative stress. We also explore therapeutic strategies targeting NOX-NOS interactions, including selective NOX inhibitors, NOS modulators, and redox homeostasis regulators, providing new insights into redox regulation and the management of metabolic neurodegenerative diseases.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"14 1","pages":"103807"},"PeriodicalIF":11.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing mitochondrial peroxynitrite biogenesis by a N-morpholinoarylimine-based iridium(III) complex in drug-induced liver cells","authors":"Lingtan Kong ,&nbsp;Ling Wang ,&nbsp;Zixi Zhang ,&nbsp;Liuqi Ye ,&nbsp;Daniel Shiu-Hin Chan ,&nbsp;Chun-Yuen Wong ,&nbsp;Jing Wang ,&nbsp;Chung-Hang Leung ,&nbsp;Wanhe Wang","doi":"10.1016/j.redox.2025.103805","DOIUrl":"10.1016/j.redox.2025.103805","url":null,"abstract":"<div><div>Peroxynitrite (ONOO⁻), a strong oxidizing agent, has an important function in the pathogenesis of various diseases, including cardiovascular, inflammatory and neurodegenerative diseases. Specifically, mitochondrial ONOO⁻ exacerbates liver injury by driving oxidative/nitrative stress and mitochondrial dysfunction, ultimately triggering dual apoptotic-necrotic hepatocyte death pathways. ONOO⁻ and its functions have been widely studied by fluorescence imaging probes, owing to their strong sensitivity, non-invasiveness, and real-time ability. However, existing probes are heavily constrained by interference from other reactive species. Herein, we describe a luminescent iridium(III) complex (<strong>1</strong>) with an <em>N</em>-morpholinoarylimine moiety as the recognition site for ONOO⁻ for imaging mitochondrial ONOO⁻. The probe shows high luminescence response to ONOO⁻ in aqueous buffer, with a luminescence enhancement of 27-fold at 100 μM ONOO⁻ and a limit of detection (LOD) of 0.65 μM, as well as high selectivity over other reactive species. Furthermore, the probe can sense both exogenous and endogenous mitochondrial ONOO⁻. Further experiments demonstrated it could visualize exogenous ONOO⁻ in 3D multicellular tumor spheroids (MCTSs) and unmask endogenous ONOO⁻ production through an NADPH oxidase 4 (NOX-4)-mediated pathway in drug-induced liver cells. This work demonstrates the potential of this strategy for developing imaging tools for probing the pathological roles of subcellar ONOO⁻ and diagnosing liver injury in the clinic.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103805"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two opposing redox signals mediated by 2-cys peroxiredoxin shape the redox proteome during photosynthetic induction","authors":"Shani Doron ,&nbsp;Nardy Lampl ,&nbsp;Alon Savidor ,&nbsp;Amir Pri-Or ,&nbsp;Corine Katina ,&nbsp;Francisco Javier Cejudo ,&nbsp;Yishai Levin ,&nbsp;Shilo Rosenwasser","doi":"10.1016/j.redox.2025.103810","DOIUrl":"10.1016/j.redox.2025.103810","url":null,"abstract":"<div><div>Photosynthetic induction, characterized by the lag in CO₂ assimilation rates during transition from darkness to light, has traditionally been attributed to Rubisco activase activity and stomatal opening. Yet, the faster induction of photosynthesis in the 2-Cys peroxiredoxins (Prxs) mutant (<em>2cpab</em>) suggested a role for oxidative signals in regulating photosynthetic rates, although the underlying molecular mechanism remains unclear. SPEAR, a redox proteomics approach, was used to systematically map redox changes occurring during photosynthesis induction and to unravel the role of 2-Cys Prxs in shaping these redox alterations. No significant difference was observed in protein expression levels between WT and <em>2cpab</em> plants, suggesting that protein abundance does not account for the <em>2cpab</em> phenotype. During the transition from dark to low light, 82 and 54 cysteine-containing peptides were reduced or oxidized, respectively, in WT plants. Most redox-regulated cysteines in photosynthetic proteins were found oxidized in the dark and became reduced in response to light. A reverse pattern was observed among redox-regulated cysteines in proteins involved in starch degradation and chloroplast glycolysis, which shifted from a reduced to an oxidized state in response to light. These findings demonstrate the initiation of two opposing redox responses, affecting distinct sets of metabolic proteins during the induction phase. Remarkably, a significantly lower number of cysteines were reduced or oxidized in <em>2cpab</em> plants, highlighting the crucial role 2-Cys Prxs play in shaping both signals. Taken together, rotational shifts between metabolic pathways during the photosynthesis induction phase are regulated by two opposing redox signals mediated by 2-Cys Prx activity.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103810"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROS-dependent localization of glycolytic enzymes to mitochondria","authors":"Pau B. Esparza-Moltó ,&nbsp;Arvind V. Goswami ,&nbsp;Süleyman Bozkurt ,&nbsp;Christian Münch ,&nbsp;Laura E. Newman ,&nbsp;Alexandra G. Moyzis ,&nbsp;Gladys R. Rojas ,&nbsp;Deann Guan ,&nbsp;Jeffrey R. Jones ,&nbsp;Fred H. Gage ,&nbsp;Gerald S. Shadel","doi":"10.1016/j.redox.2025.103812","DOIUrl":"10.1016/j.redox.2025.103812","url":null,"abstract":"<div><div>Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted <span>d</span>-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103812"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144827048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis triggers anti-tumor immunity via promoting chaperone-mediated autophagic degradation of SHP2","authors":"Jiazhen Zhu ,&nbsp;Xiaofei Li ,&nbsp;Wenbo Chen ,&nbsp;Zhenqi Zuo ,&nbsp;Qin Gong ,&nbsp;Jinbo Hu ,&nbsp;Kai Huang ,&nbsp;Wen Liu ,&nbsp;Yanhong Gu ,&nbsp;Qiang Xu ,&nbsp;Wenjie Guo","doi":"10.1016/j.redox.2025.103796","DOIUrl":"10.1016/j.redox.2025.103796","url":null,"abstract":"<div><div>Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, plays a significant role in various physiological and pathological processes, including cancer. However, the connection between ferroptosis and anti-tumor immunity remains incompletely understood. Our investigation demonstrates that ferroptosis inducers like RSL3 can enhance the efficacy of <em>anti</em>-PD-1 therapy by activating the STAT1 signaling pathway. Mechanistically, RSL3 activates the tyrosine phosphatase SHP2 in cancer cells and facilitates its degradation through chaperone-mediated autophagy mediated by the KFERQ motif from residues 530 to 534. This enhances cancer cells’ sensitivity to IFN-γ, leading to increased phosphorylation and nuclear translocation of STAT1 and higher expression of major histocompatibility complex class I (MHC I). Consequently, this heightened sensitivity correlates with increased susceptibility to T cell-mediated cytotoxicity. In vivo studies showed that RSL3 treatment reduced SHP2 expression within tumor tissues and bolstered anti-tumor immunotherapy by promoting increased T cell infiltration and function. The combination of RSL3 and <em>anti</em>-PD-1 antibody demonstrates superior therapeutic efficacy in controlling tumor growth compared to monotherapy. Our study not only elucidates a previously unrecognized link between ferroptosis and anti-tumor immunity but also presents a rationale for combining ferroptosis inducers with immune checkpoint inhibitors in cancer treatment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103796"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asparagine synthetase modulates glutaminase inhibitor sensitivity through metabolic reprogramming and serves as a prognostic biomarker in hepatocellular carcinoma.","authors":"Benjian Gao,Dongning Zheng,Hong Liu,Yu Guo,Yuntao Ye,Zhou Chen,Fengyi Yang,Jie Liu,Guangnian Zhang,Guoying Feng,Yongfa Liu,Qiang Wang,Song Su,Xiaoli Yang,Bo Li","doi":"10.1016/j.redox.2025.103813","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103813","url":null,"abstract":"Glutamine addiction represents a metabolic vulnerability in hepatocellular carcinoma (HCC), making glutaminase inhibitor CB-839 therapy a promising approach. However, effective therapeutic strategies are not yet available. In this study, we aim to investigate the potential role of asparagine synthetase (ASNS) as a target for HCC therapy during CB-839 treatment. CB-839 suppressed HCC cell growth, triggered apoptosis, and induced oxidative stress along with the disruption of amino acid metabolism. Moreover, ASNS was induced by CB-839 treatment through the activation of the amino acid response pathway. ASNS was significantly upregulated in HCC tumor tissues and was positively associated with poor prognosis; indeed our results revealed that its overexpression facilitated the proliferation, migration, and invasion of HCC cells. Furthermore, ASNS increased glutaminolysis and glutathione synthesis through reprogramming glutamine metabolism to maintain intracellular redox homeostasis, thereby activating the mTOR pathway that contributed to HCC progression. ASNS knockdown sensitized HCC cells to CB-839 both in vitro and in vivo. Overall, ASNS modulated the sensitivity to CB-839 in HCC through metabolic reprogramming, potentially serving as a biomarker for CB-839 response and a promising therapeutic target for HCC.","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"7 1","pages":"103813"},"PeriodicalIF":11.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic dysfunction-associated steatohepatitis reduces hepatic H2S-producing enzymes altering persulfidome composition","authors":"Tzu Keng Shen ,&nbsp;Thibaut Vignane ,&nbsp;Eduardo H. Gilglioni ,&nbsp;Leonardo Traini ,&nbsp;Elisavet Kalaitsidou ,&nbsp;Pierre Conan ,&nbsp;Ao Li ,&nbsp;Wadsen St-Pierre-Wijckmans ,&nbsp;Jose M. Herranz ,&nbsp;Bernat Elvira ,&nbsp;Lukas Otero Sanchez ,&nbsp;Eric Trépo ,&nbsp;Leo Deelman ,&nbsp;Wei Wu ,&nbsp;Milos R. Filipovic ,&nbsp;Joris Messens ,&nbsp;Daria Ezeriņa ,&nbsp;Esteban N. Gurzov","doi":"10.1016/j.redox.2025.103809","DOIUrl":"10.1016/j.redox.2025.103809","url":null,"abstract":"<div><div>Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive disease driven by obesity-related hepatic inflammation and oxidative stress. Recently, cysteine persulfidation (PSSH), a protective post-translational modification by hydrogen sulfide (H₂S), was established to play a role in redox regulation. Despite the role of the liver in H₂S metabolism, the function of PSSH in MASH remains underexplored. We demonstrated that H₂S-producing enzymes are downregulated in both human and mouse livers with steatosis and fibrosis, resulting in a decline in global PSSH levels. Dimedone-switch mass spectrometry in dietary mouse models of distinct obesity-associated liver disease stages revealed dysregulated PSSH on specific proteins. Surprisingly, increased hepatic PSSH levels of protein tyrosine phosphatases and redox regulators were found in advanced disease stages, suggesting a targeted adaptive response to oxidative stress. Overall, our findings demonstrated that impaired H₂S production disrupts protective PSSH networks in MASH. However, selective PSSH preservation on redox-sensitive proteins may represent a compensatory mechanism, underscoring the therapeutic potential of persulfidation in restoring redox homeostasis during obesity-associated chronic liver disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103809"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP/Nrf2 suppresses ferroptosis to alleviate acute lung injury induced by intestinal ischemia/reperfusion","authors":"Lu Tang ,&nbsp;Chengjie Yang ,&nbsp;Yanhua Peng ,&nbsp;Mudi Liu ,&nbsp;Na Wei ,&nbsp;Xin Fan ,&nbsp;Bo Yang ,&nbsp;Jing Jia ,&nbsp;Ye Chen ,&nbsp;Jianguo Feng ,&nbsp;Jun Zhou","doi":"10.1016/j.redox.2025.103811","DOIUrl":"10.1016/j.redox.2025.103811","url":null,"abstract":"<div><div>Intestinal ischemia reperfusion (II/R) injury is a common critical disease with high morbidity and mortality. The mechanism of II/R-induced acute lung injury (ALI) is not fully elucidated. Yes-associated protein (YAP), a downstream transcriptional coactivator of the Hippo signaling pathway, plays a central role in controlling organ development and cell proliferation. However, whether YAP is involved in regulating II/R-induced ALI remains to be further explored. This study aimed to investigate the regulatory role of YAP in ALI and ferroptosis caused by II/R, and to explore whether YAP exerts anti-ferroptosis and anti-inflammatory effects by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry and upregulating Nrf2 expression. In vivo models demonstrated that overexpression of YAP inhibited II/R-induced ALI and ferroptosis. This was evident through the upregulation of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and Nrf2 expression, as well as the mitigation of characteristic mitochondrial ferroptosis changes in lung type II epithelial cells. Additionally, YAP overexpression protected against II/R-induced ALI in mice, leading to notable improvements in lung pathology, reduced pulmonary edema, and decreased lung inflammation. Consistent conclusions were also reached in vitro models. It was observed that overexpression of YAP inhibited ferroptosis and oxidative stress by increasing Nrf2 expression and promoting its nuclear translocation. Additionally, it was discovered that knocking down Nrf2 resulted in the abolition of YAP-mediated ferroptosis alleviation in MLE-12 cells. Based on our findings, we can infer that YAP inhibits ferroptosis by upregulating Nrf2 expression and promoting its translocation into the nucleus, thereby ameliorating oxidative stress and lung injury along with the systemic inflammatory response following II/R. Furthermore, we propose that targeting YAP could be a promising approach for the treatment of ALI by suppressing ferroptosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103811"},"PeriodicalIF":11.9,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}