Life sciences最新文献

{"title":"Dose-dependent effects of vildagliptin (DPP-4 inhibitor) in a scopolamine-induced memory impairment model in rats","authors":"Fazilet Şen Metin ,&nbsp;Elif Aksöz","doi":"10.1016/j.lfs.2026.124245","DOIUrl":"10.1016/j.lfs.2026.124245","url":null,"abstract":"<div><h3>Aims</h3><div>Cognitive decline and dementia are closely linked with metabolic disorders such as type 2 diabetes mellitus, sharing common pathophysiological mechanisms including insulin resistance, inflammation, and oxidative stress. This study investigated the neuroprotective potential of vildagliptin, an antidiabetic medication, in a rat model of scopolamine-induced acute memory impairment, focusing on its effects on learning and memory as well as its association with cholinergic activity, inflammatory responses, and lipid peroxidation as an indicator of oxidative stress.</div></div><div><h3>Materials and methods</h3><div>Male Wistar Albino rats were orally administered vildagliptin (0.5, 5, or 50 mg/kg/day) or physiological saline for 4 weeks. Spatial learning and memory were assessed using the Morris water maze (MWM) test. Memory impairment was induced by intraperitoneal injection of scopolamine (1 mg/kg, <em>i.p.</em>) before the probe trial of the MWM. Following behavioral testing, rats were sacrificed, and hippocampal tissues were isolated for biochemical analysis.</div></div><div><h3>Key findings</h3><div>Vildagliptin significantly enhanced spatial learning performance in a dose-dependent manner during the acquisition phase of the MWM. Scopolamine administration markedly impaired memory performance in rats. Pretreatment with vildagliptin at all tested doses prevented these memory deficits during the MWM probe trial. In addition, vildagliptin robustly prevented scopolamine-induced increases in hippocampal acetylcholinesterase (AChE) activity and elevated levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA).</div></div><div><h3>Significance</h3><div>These findings suggest that vildagliptin may exert protective effects against cognitive impairment by modulating cholinergic activity, inflammatory responses, and lipid peroxidation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124245"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational sevoflurane exposure induces amino acid metabolic reprogramming and cognitive deficits in offspring","authors":"Jieyu Ma ,&nbsp;Li Xu ,&nbsp;Nai Sun ,&nbsp;Jianqiang Song ,&nbsp;Jie Wang ,&nbsp;Jingjing Wang ,&nbsp;Liumei Li ,&nbsp;Qinjun Chu ,&nbsp;Lin-jian Wang ,&nbsp;Qiong Song","doi":"10.1016/j.lfs.2026.124246","DOIUrl":"10.1016/j.lfs.2026.124246","url":null,"abstract":"<div><h3>Background</h3><div>Sevoflurane is one of the most widely used anesthetics in pediatric medicine; however, accumulating evidence raises critical concerns regarding its potential to induce long-term neurodevelopmental deficits. Despite extensive research, the underlying systemic molecular mechanisms driving these outcomes remain elusive.</div></div><div><h3>Methods</h3><div>Pregnant C57BL/6J mice were exposed to 2.5% sevoflurane for 2 h at embryonic day 14 (E14). Offspring were assessed for spatial learning and anxiety-related behaviors. To reconstruct the molecular landscape of toxicity, we employed an integrative multi-omics approach combining transcriptomics, proteomics, and paired brain–serum metabolomics, complemented by ELISA validation and histopathology.</div></div><div><h3>Results</h3><div>Sevoflurane-exposed offspring exhibited persistent spatial learning deficits and anxiety-like behaviors. These functional impairments were mirrored by histopathological damage, characterized by disordered neuronal arrangement and reduced Nissl-positive cells in the hippocampus. Consistently, ELISA analysis revealed a pronounced systemic inflammatory response (elevated IL-1β, IL-6, TNF-α). Integrated multi-omics profiling uncovered the molecular basis of these phenotypes, revealing a landscape of neurodevelopmental gene suppression alongside the activation of oxidative stress and inflammatory signaling. Underpinning these multidimensional pathologies, we identified a convergent reprogramming of amino acid metabolism, defined by glutamate depletion and lysine accumulation—metabolic shifts previously implicated in neuroinflammation and cognitive decline. Finally, ectoine and 5-OPPA were consistently depleted in both brain and serum, identifying them as novel concordant biomarkers of anesthetic neurotoxicity.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that gestational sevoflurane exposure induces persistent neurocognitive dysfunction in offspring driven by amino acid metabolic reprogramming. The concordant depletion of ectoine and 5-OPPA highlights their potential as minimally invasive biomarkers for anesthetic induced neurodevelopmental injury.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124246"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A protective role of ECSIT in chemotherapy-induced intestinal mucositis by maintaining Lgr5+ intestinal stem cells and gut homeostasis","authors":"Shuai Wang ,&nbsp;Yuying Jiang ,&nbsp;Jie Yu ,&nbsp;Pingping Cao ,&nbsp;Yan Chen ,&nbsp;Tianqi Shen ,&nbsp;Jukun Zhang ,&nbsp;Shuo Yang ,&nbsp;Ping Wang ,&nbsp;Fan Lin ,&nbsp;Yingjian Zhang","doi":"10.1016/j.lfs.2026.124236","DOIUrl":"10.1016/j.lfs.2026.124236","url":null,"abstract":"<div><h3>Aims</h3><div>Chemotherapy-induced intestinal mucositis (CIM) is a common and severe side effect linked to disrupted intestinal stem cell (ISC) balance, though its molecular regulation remains unclear. The principal objective of this research was to elucidate the role of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in intestinal stem cell balance and mucosal repair during CIM, with a specific focus on the Wnt/β-catenin pathway.</div></div><div><h3>Materials and methods</h3><div>This study used multi-omics and gene editing to elucidate ECSIT's role in intestinal stem cell balance and mucosal repair via the Wnt/β-catenin pathway. Multi-omics and Gene Set Enrichment Analyses (GSEA) identified ECSIT as a key CIM regulator.</div></div><div><h3>Key findings</h3><div>Chemotherapeutic drugs dose-dependently reduced ECSIT expression in intestinal epithelial cells. Clinical analysis revealed that ECSIT expression decreased with increasing pathological severity (normal &gt; inflammation &gt; adenocarcinoma). In intestinal epithelium-specific knockout mice, ECSIT deficiency worsened irinotecan (CPT11)-induced CIM and blocked β-catenin nuclear translocation. ECSIT stabilized the β-catenin complex, regulating Wnt target genes like Axis inhibition protein (<em>AXIN</em>) and Cyclin D1 (<em>CCND1</em>); its knockout reduced Wnt signaling. Single-cell sequencing (scRNA-seq) revealed that ECSIT knockout reduced Lgr5 stem cells and increased inflammatory cell infiltration. Lgr5-specific inducible knockout and ECSIT complementation demonstrated that restoring ECSIT reversed β-catenin inhibition and improved CIM pathology.</div></div><div><h3>Significance</h3><div>This study clarified ECSIT's dual role in stabilizing β-catenin and sustaining Wnt signaling—regulating Lgr5 intestinal stem cell proliferation and differentiation, epithelial renewal, and immune balance. These findings offer insights into CIM pathogenesis and establish the basis for developing targeted therapy through ECSIT-Wnt axis regulation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124236"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HHcy promotes hypertension by activating ferroptosis via suppression of the renal H₂S-SLC7A11/GPX4 axis","authors":"Pan Huang ,&nbsp;Kexin Zhang ,&nbsp;Ying Chen ,&nbsp;Jiaxin Cheng ,&nbsp;Shuangshuang Yang ,&nbsp;Lin Shi ,&nbsp;Yajuan Wang ,&nbsp;Qin Zhang","doi":"10.1016/j.lfs.2026.124247","DOIUrl":"10.1016/j.lfs.2026.124247","url":null,"abstract":"<div><div>Elevated homocysteine (Hcy) is an independent risk factor for hypertension, and kidney is an important organ for Hcy metabolism and blood pressure regulation, and its damage is closely related to the process of hypertension. Recent evidence suggests that ferroptosis, an oxidative stress-related form of cell death, contributes significantly to hypertensive organ damage. However, whether Hcy aggravates renal injury in H-type hypertension by destroying renal hydrogen sulfide (H₂S) metabolism and driving ferroptosis is still lack of direct evidence. In this study, the H-type hypertensive rat model induced by high methionine diet combined with HK-2 cell model was studied. We observed a significant increase in blood pressure and plasma Hcy in the Hcy group, accompanied by renal dysfunction and renal tubular injury. Specifically, in the renal tissue of Hcy group rats, the levels of KIM-1, Fe²⁺ and malondialdehyde (MDA) were increased, glutathione/glutathione disulfide (GSH/GSSG) ratio decreased, SLC7A11 expression was down-regulated, and GPX4 activity was inhibited. Concurrently, H₂S levels and cystathionine-beta-synthase (CBS) activity were decreased. In vitro experiments using HK-2 cells confirmed that Hcy could down-regulate the expression of CBS, cystathionine-gamma-lyase (CSE), SLC7A11, GPX4 and GSH/GSSG ratio, and up-regulate MDA and reactive oxygen species (ROS) levels. Treatment with H₂S donor (NaHS) or ferroptosis inhibitors (Ferrostatin-1, Fer-1) could rescue these changes. Collectively, our results demonstrate that high Hcy promotes hypertension by suppressing endogenous H₂S generation, downregulating the SLC7A11/GPX4 signaling axis, and inducing ferroptosis. These findings reveal a new mechanism by which Hcy aggravates hypertension by inhibiting H₂S synthesis and inducing ferroptosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124247"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages, fibrosis, and intrauterine adhesions: Cellular interactions and pathophysiological implications","authors":"Xingyu Jia ,&nbsp;Yunfei Zhang ,&nbsp;Huihua Cai","doi":"10.1016/j.lfs.2026.124242","DOIUrl":"10.1016/j.lfs.2026.124242","url":null,"abstract":"<div><div>Intrauterine Adhesion (IUA) is a pathological condition caused by damage to the basal layer of the endometrium, often triggered by uterine surgeries such as curettage or intrauterine infections. It is primarily characterized that the normal endometrial tissue is replaced by intrauterine fibrosis and adhesion formation, leading to menorrhagia, amenorrhea, infertility, and recurrent pregnancy loss. Emerging evidence underscores macrophages as central orchestrators of fibrotic progression in IUA, modulating cytokine cascades (e.g., TGF-β/Smad) and ECM remodeling through dynamic polarization shifts (M1/M2). In the early stages of IUA, M1 macrophages are activated by pro-inflammatory signals and secrete cytokines such as TNF-α and IL-1β. These factors amplify the inflammatory response, aggravate tissue damage, and impede endometrial repair. Conversely, during the repair phase, M2 macrophages are activated in response to anti-inflammatory signals. M2 macrophages secrete TGF-β, IL-10, and other pro-repair mediators, which promote fibroblast activation and their myofibroblast transdifferentiation, key cells responsible for ECM production. However, overactivation of M2 macrophages and excessive production of TGF-β result in uncontrolled ECM accumulation, driving progressive fibrosis and adhesion formation. This review aims to explore the mechanistic link between macrophage activation and fibrotic pathways in IUA. Emerging therapeutic strategies targeting macrophage plasticity including nanoparticle-mediated polarization modulation and cytokine axis inhibition, offer promising avenues for reducing fibrosis and improving clinical outcomes in patients with IUA.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124242"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise alleviates the obesity-related dysfunction of skeletal muscle and heart caused by Akh gene knockdown in Drosophila","authors":"Ying Lin ,&nbsp;Deng-tai Wen ,&nbsp;Qing-yao Sun ,&nbsp;Shou-zhi Lv ,&nbsp;Ji-ying Wang ,&nbsp;Xing-feng Ma","doi":"10.1016/j.lfs.2026.124237","DOIUrl":"10.1016/j.lfs.2026.124237","url":null,"abstract":"<div><div>The Adipokinetic hormone (Akh), a functional analog of mammalian glucagon, plays a key role in regulating energy metabolism in <em>Drosophila</em>. Although exercise is recognized as an important intervention for preventing and alleviating obesity-related complications, its efficacy against obesity induced by <em>Akh</em> gene deficiency remains unclear. In this study, the <em>Akh</em> gene was knocked down systemically and specifically in the corpora cardiaca (CC) using <em>Act-gal4/Akh-UAS-RNAi</em> and <em>Akh-gal4/Akh-UAS-RNAi</em> systems in flies, and these flies were followed by a two-week exercise intervention. The results showed <em>Akh</em> knockdown induced obesity phenotypes, including significantly increased body weight and triglyceride levels, and concurrently impaired skeletal muscle and cardiac function—manifested as reduced climbing speed, climbing endurance, and cardiac shortening fraction, along with elevated heart rate. Mechanistically, these effects were associated with upregulated systemic <em>FASN1</em>/<em>Mdy</em>/triglyceride process and lipotoxicity (MDA), as well as downregulated mitochondrial (<em>PGC-1α</em>) and contractile (<em>Mhc</em>) markers in muscle. Exercise intervention ameliorated the obesity phenotype and was correlated with increased <em>Akh</em> expression. These findings confirm that <em>Akh</em> gene deficiency contributes to hereditary obesity and obesity-related dysfunction of skeletal muscle and heart, and demonstrate that exercise can serve as a therapeutic strategy to counteract impairments resulting from <em>Akh</em> knockdown, suggesting its potential relevance for treating human obesity linked to glucagon-related genetic defects.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124237"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOSL2+ macrophages drive pro-inflammatory phenotype via miR-92a-3p/FOSL2/NF-κB axis to mediate endothelial cell injury in aortic dissection","authors":"Zhenpeng Yuan ,&nbsp;Ruihan Chen ,&nbsp;Rong Fan ,&nbsp;Zhenyu Yang ,&nbsp;Qianqian Zhu ,&nbsp;Chenyang Qiu ,&nbsp;Ziheng Wu ,&nbsp;Donglin Li ,&nbsp;Yangyan He ,&nbsp;Hongkun Zhang","doi":"10.1016/j.lfs.2025.124174","DOIUrl":"10.1016/j.lfs.2025.124174","url":null,"abstract":"<div><h3>Background</h3><div>In aortic dissection, macrophages play a critical role; however, the impact of macrophages on vascular endothelial cells remains unclear.</div></div><div><h3>Methods</h3><div>By constructing macrophage cell lines with stable overexpression and knockdown of FOSL2, M1 polarization was induced to evaluate the effects of FOSL2 on macrophage polarization, pro-inflammatory cytokine expression, macrophage migration, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial function. Additionally, co-culture experiments were conducted to study the effects of macrophages with FOSL2 overexpression and knockdown on the proliferation, migration, apoptosis, and signaling pathways of mouse aortic endothelial cells (MAECs). Furthermore, miRNA prediction and validation experiments were performed to explore the regulatory mechanism of miR-92a-3p on FOSL2 and its role in macrophage-endothelial cell interactions.</div></div><div><h3>Results</h3><div>Overexpression of FOSL2 enhanced the expression and secretion of pro-inflammatory cytokines, promoting the M1 phenotype. It also increased macrophage migration, apoptosis, and ROS generation while suppressing mitochondrial membrane potential and activating the MYD88/TLR4/NF-κB signaling pathway. In co-culture experiments, FOSL2 overexpression in macrophages inhibited the proliferation and migration of co-cultured MAECs, promoted apoptosis and mitochondrial dysfunction, and upregulated endothelial injury markers and the PI3K/AKT/NF-κB signaling pathway. miR-92a-3p was downregulated during M1 polarization and directly targeted FOSL2, inhibiting its expression. Overexpression of miR-92a-3p reversed the FOSL2-mediated M1 polarization of macrophages and the functional impairment of co-cultured endothelial cells.</div></div><div><h3>Conclusion</h3><div>FOSL2 promotes macrophage M1 polarization by regulating the MYD88/TLR4/NF-κB signaling pathway, enhancing pro-inflammatory responses, and inhibiting the function of co-cultured endothelial cells. miR-92a-3p exerts the opposite effect by targeting FOSL2, suppressing M1 polarization and endothelial cell injury.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124174"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ–STAT1 signaling","authors":"Laiping Zhang ,&nbsp;Jie Liu ,&nbsp;Xiao Guan ,&nbsp;Boshi Liu ,&nbsp;Ying Liu ,&nbsp;Weinian Shou ,&nbsp;Xin Chen ,&nbsp;Xiaohui Li ,&nbsp;Dayan Cao","doi":"10.1016/j.lfs.2026.124212","DOIUrl":"10.1016/j.lfs.2026.124212","url":null,"abstract":"<div><h3>Aims</h3><div>With the extensive application of immunotherapy in treating cancer, the immunotherapy-related cardiovascular toxicity (ITR-CVT) has gotten a rapid recognition due to its high mortality. Previously, we have found that potential cancer immunotherapies based on promoting iNKT cell activation exacerbate ISO-induced cardiac injury, but the underlying mechanism is unknown. The current study is to determine which specific cell type/s and the corresponding molecular pathways are responsible for such a cardiotoxicity.</div></div><div><h3>Materials and methods</h3><div>Transcriptome sequencing and bioinformatic analysis were performed on heart tissues from an enhanced cardiac injury model following iNKT cell activation via α-Galactosylceramide (αGC). The role of IFN-γ–STAT1 signaling was validated using IFN-γ antibody blocking and JAK-STAT1 chemical inhibition. The experiments of Macrophage isolation and depletion were conducted to assess cell-specific contributions. In vitro co-culture experiments with αGC-primed macrophages and fibroblasts were conducted under STAT1 inhibition or silencing. Tumor-bearing mice were also examined.</div></div><div><h3>Key findings</h3><div>Transcriptome analysis identified IFN-γ–STAT1 signaling as central to the enhanced cardiac injury, blocking IFN-γ or inhibiting STAT1 could attenuate the injury. Macrophages were identified as the main source of IFN-γ–STAT1 activation, and their depletion significantly reversed cardiac injury exacerbation. In vitro, STAT1 inhibition or silencing reduced fibroblast activation induced by αGC-primed macrophages. In tumor-bearing mice, αGC also further exacerbated cardiac injury.</div></div><div><h3>Significance</h3><div>These findings revealed that the activation of STAT1 in cardiac macrophages via IFNγ critically contributes to cardiotoxicity induced by iNKT-immunotherapy, which provides a potential method to manage ITR-CVT in patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124212"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing reveals the role of neutrophils in intestinal ischemia-reperfusion injury in mice","authors":"Ran Li ,&nbsp;Ao Wang ,&nbsp;Jiayi Cao ,&nbsp;Kehui Li ,&nbsp;Hao Zhang ,&nbsp;Yiwen Wang ,&nbsp;Simiao Chen ,&nbsp;Mengmeng Zhuang ,&nbsp;Chao Meng ,&nbsp;Wensheng Wang ,&nbsp;Yong Sun","doi":"10.1016/j.lfs.2026.124208","DOIUrl":"10.1016/j.lfs.2026.124208","url":null,"abstract":"<div><h3>Objective</h3><div>Intestinal ischemia-reperfusion injury (IRI) severely compromises the mucosal barrier. While neutrophils are key responders, their specific roles and mechanisms remain unclear. This study aims to delineate the functional heterogeneity of neutrophils in intestinal IRI and identify the underlying molecular pathways.</div></div><div><h3>Methods</h3><div>A murine model of intestinal IRI was established by subjecting C57BL/6 mice to 45 min of ischemia and 4 h of reperfusion. Single-cell RNA sequencing (scRNA-seq) was performed on intestinal tissues. Neutrophil depletion, co-culture assays, and pharmacological modulation of endoplasmic reticulum stress (ERS) were employed for functional validation.</div></div><div><h3>Results</h3><div>scRNA-seq analysis revealed a significant expansion of neutrophils and inflammatory monocytes alongside a reduction in lymphocytes post-IRI. Notably, we identified a distinct pro-inflammatory neutrophil subcluster (C5), characterized by high expression of Atf4 and ERS-related genes. In vivo neutrophil depletion markedly alleviated intestinal damage, evidenced by improved histology, reduced serum DAO and IL-6 levels, and preserved Occludin expression. Mechanistically, neutrophils were shown to exacerbate injury via the ERS pathway. Pharmacological induction (tunicamycin) or inhibition (4-PBA) of ERS significantly augmented or mitigated IRI severity, respectively, with ATF4 playing a central role.</div></div><div><h3>Conclusion</h3><div>This study identifies a pathogenic neutrophil subpopulation that drives intestinal IRI through the ATF4-mediated ERS pathway. These findings provide new insights into the immunopathology of IRI and highlight ATF4 or specific neutrophil subsets as potential therapeutic targets for mitigating intestinal damage.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124208"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From inflammation to innovation: Exploring the emerging roles of itaconate in ARDS","authors":"Guixiang Yang ,&nbsp;Ling Hu ,&nbsp;Min Zhong ,&nbsp;Xia Huang ,&nbsp;Jianhua Li","doi":"10.1016/j.lfs.2026.124209","DOIUrl":"10.1016/j.lfs.2026.124209","url":null,"abstract":"<div><div>Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure characterized by diffuse alveolar damage, pulmonary edema, and decreased lung compliance. It represents the most severe manifestation of acute lung injury (ALI). Conditions such as sepsis, acute pancreatitis, and trauma are well-recognized triggers of ALI/ARDS. Given the high mortality rate and limited therapeutic options, current management strategies primarily rely on lung-protective ventilation, careful fluid management, and pharmacological interventions. Consequently, there is an urgent need to develop novel and more effective therapeutic approaches. Itaconate, a metabolite generated during immune cell activation, exhibits potent anti-inflammatory and antioxidant properties. Emerging evidence suggests that itaconate confers protective effects in various inflammatory diseases. This review explores the mechanisms and functions of itaconate in the context of ARDS, providing new insights into its potential as a therapeutic agent.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124209"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}