Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"The role of cytokines in cytokine release syndrome (CRS) after CAR T cell therapy","authors":"Kathrin Gabriel ,&nbsp;Lucie Heinzerling ,&nbsp;Louisa von Baumgarten ,&nbsp;Marion Subklewe ,&nbsp;Sebastian Kobold","doi":"10.1016/j.bbamcr.2026.120115","DOIUrl":"10.1016/j.bbamcr.2026.120115","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for hematological malignancies. However, cytokine release syndrome (CRS) remains a common and potentially severe toxicity, significantly affecting patient safety and requiring intensive clinical management. This review provides a focused synthesis on the role of cytokines in CRS after CAR T cell therapy, integrating recent mechanistic insights with clinical implications. We delineate the cellular and molecular pathways involving key cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), describing their sources, downstream signaling events, and effects on target tissues. By bridging basic cytokine biology with clinical aspects and therapeutic strategies, this review aims to provide a comprehensive framework for understanding the role of cytokines in CRS pathophysiology, ultimately supporting the development of safer and more effective CAR T cell therapies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120115"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shielding retinal pigment epithelium cells from high glucose-induced oxidative stress: the protective effect of phospholipase D (PLD) pathway inhibition","authors":"María S. Echevarría ,&nbsp;Paula E. Tenconi ,&nbsp;Vicente Bermúdez ,&nbsp;Jorgelina M. Calandria ,&nbsp;Nicolas G. Bazan ,&nbsp;Melina V. Mateos","doi":"10.1016/j.bbamcr.2026.120121","DOIUrl":"10.1016/j.bbamcr.2026.120121","url":null,"abstract":"<div><div>The retinal pigment epithelium (RPE) performs key roles in preserving retinal integrity and must continuously manage oxidative stress (OS). We previously demonstrated that the canonical phospholipase D isoforms, PLD1 and PLD2, mediate the RPE inflammatory response triggered by inflammatory injury. This study explores the mechanisms of modulation of OS mediated by PLD inhibition in RPE cells exposed to high glucose (HG) levels.</div><div>ARPE-19, D407 and the novel human RPE cell line ABC were cultured under HG (33 mM) or normal glucose (NG, 5.5 mM) conditions. To inhibit PLD1, PLD2, and NADPH oxidase (NOX), VU0359595 (PLD1i), VU0285655-1 (PLD2i), and diphenyleneiodonium chloride (DPI) were used, respectively. HG exposure significantly increased reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential (MMP) in ARPE-19 and D407 cells. These effects were prevented by PLD1i and PLD2i in an Nrf-2 and cyclooxygenase-2 -independent manner. In ARPE-19 cells, DPI prevented OS induced by HG as well as the stress triggered by the combination of phosphatidic acid + diacylglycerol, bioactive lipids generated through the PLD pathway-. Similarly, HG elevated ROS levels in ABC cells, and this increase was prevented by PLD1i and DPI. RNAseq analysis showed differential expression of NOX family members (NOX1,2 and 4 and DUOX1 and 2) in ARPE-19 and ABC cells.</div><div>Our results demonstrate that PLDs inhibition prevent HG-induced OS in RPE cells, possibly by reducing NOX activity. The PLD pathway constitutes a novel pharmacological target to simultaneously mitigate OS and the inflammatory response, two hallmarks of retinal degenerative diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120121"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines","authors":"Shannon McMahon ,&nbsp;Dezerae Cox ,&nbsp;Flora Cheng ,&nbsp;Albert Lee ,&nbsp;Justin.J. Yerbury ,&nbsp;Heath Ecroyd","doi":"10.1016/j.bbamcr.2026.120124","DOIUrl":"10.1016/j.bbamcr.2026.120124","url":null,"abstract":"<div><div>Maintaining proteome integrity is essential for cellular function and survival. Disruptions in proteostasis lead to the aggregation of proteins into inclusions, a process that underlies many neurodegenerative diseases. To quantitatively assess the proteostasis capacity of neuronal cells, we employed an aggregation-prone double mutant form of firefly luciferase (denoted Fluc^DM) as a reporter protein. We compared two commonly used neuronal cell lines, mouse neuroblastoma cells (Neuro-2a) and a motor neuron-like hybrid line (NSC-34), to evaluate their ability to prevent the aggregation of proteins into intracellular inclusions. We observed a significantly greater propensity of Fluc^DM to form inclusions in NSC-34 cells compared to Neuro-2a cells. This suggests a reduced capacity of NSC-34 cells for managing aggregation-prone proteins. Proteomic profiling of Fluc^DM inclusions purified from both cell types revealed cell-type-specific engagement of the proteostasis machinery with aggregation-prone proteins. Comparing the proteomic profiles of key arms of the proteostasis network between these two cell lines revealed that the endoplasmic reticulum (ER) unfolded protein response is differentially expressed. This study establishes a quantitative platform for assessing cellular proteostasis capacity and underscores the importance of cell-type context in proteome maintenance. These insights have implications for understanding the selective vulnerability of neurons in protein misfolding disorders.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120124"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAM10 and ADAM17 differently mediate induced pulmonary ACE release by either direct proteolysis or indirect upregulation protein synthesis","authors":"Yan Yu ,&nbsp;Aaron Babendreyer ,&nbsp;Alessa Pabst ,&nbsp;Anna Michely ,&nbsp;Marie Tauscher ,&nbsp;Christian Martin ,&nbsp;Mark P. Kühnel ,&nbsp;Danny D. Jonigk ,&nbsp;Stefan Düsterhöft ,&nbsp;Andreas Ludwig","doi":"10.1016/j.bbamcr.2026.120112","DOIUrl":"10.1016/j.bbamcr.2026.120112","url":null,"abstract":"<div><div>Angiotensin-converting enzyme (ACE) is expressed on lung endothelium and can promote hypertension and cardiovascular diseases. By the activity of the metalloproteinase ADAM10 ACE can be constitutively released from the cell membrane as soluble protease. The aim of this study was to further investigate the mechanisms underlying the enhanced production of soluble ACE under pathological conditions. Using in vitro models of primary human pulmonary microvascular endothelial cells (HPMECs) and primary human umbilical vein endothelial cells (HUVECs), as well as ex vivo models of human and murine precision-cut lung slices (PCLS), we examined ACE release in response to inflammatory stimuli, hypoxia, and protein kinase C (PKC) activation, in the presence or absence of ADAM10 and ADAM17 inhibitors. Our findings demonstrate that ADAM10 is the primary sheddase responsible for inducible ACE release, while ADAM17 contributes to ACE shedding via paracrine transcriptional induction through soluble mediators. Moreover, ACE release was differentially induced by lipopolysaccharide (LPS) and hypoxia in a manner dependent on the cellular or tissue context and exhibited species-specific differences in response to the tested stimuli. Importantly, inducibly released ACE displays enhanced catalytic activity attributable to its increased extracellular concentration. Collectively, our data reveal, for the first time, that inducible ACE release is directly mediated by ADAM10, indirectly facilitated by ADAM17, and is influenced by tissue-, context-, and species-dependent factors. This complex regulation of soluble ACE release in pathological settings may be involved in fine tuning vascular pathologies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120112"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sox9-dependent acquisition of a drug resistant “memory state” induces reciprocal expression of Sox6 and Sox7 in BRAF melanoma","authors":"John Abou-Hamad ,&nbsp;Samuel Delisle ,&nbsp;Brennan Garland ,&nbsp;Mohammed Hersi ,&nbsp;David Cook ,&nbsp;Luc A. Sabourin","doi":"10.1016/j.bbamcr.2026.120118","DOIUrl":"10.1016/j.bbamcr.2026.120118","url":null,"abstract":"<div><div>In melanoma, SOX9 and SOX10 are markers of the mesenchymal and melanocytic state, respectively. Using a panel of BRAF^V600E positive YUMM lines, we find that, following chronic vemurafenib treatment, SOX10 is lost whereas SOX9 is induced. Overexpression or knock-down of either SOX9 or SOX10 had no impact on vemurafenib sensitivity. However, we find that SOX9 is necessary to program a vemurafenib-resistance memory state following a drug holiday in vitro. RNA-Seq studies show that the loss of <em>Sox10</em> represents an intermediate state that is accompanied by the loss of <em>Sox6</em> and the induction of <em>Sox7, Sox9</em> and other phenotype switching markers. However, SOX7 expression is not sufficient to induce vemurafenib resistance. Upon acquired drug resistance, we observed differential chromatin accessibility in the <em>Sox9</em> and <em>Sox10</em> upstream regions, supporting their activation and repression, respectively. Overall, our data show that the loss of SOX10 and SOX9 induction are critical to program drug resistance. Furthermore, we show that the YUMM cell lines represent a good murine model to investigate transitions to an acquired drug resistant state.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120118"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix stiffness-induced NARF promotes hepatocellular carcinoma progression by enhancing LEF1-mediated transcription","authors":"Xuelian Xiao,&nbsp;Kangsheng Tu","doi":"10.1016/j.bbamcr.2026.120122","DOIUrl":"10.1016/j.bbamcr.2026.120122","url":null,"abstract":"<div><div>Liver fibrosis and cirrhosis generate a stiff extracellular matrix (ECM) niche that is closely associated with hepatocellular carcinoma (HCC) initiation and progression. Although multiple pathways and molecules are implicated in ECM rigidity-induced mechanical force transduction, the precise mechanism by which ECM rigidity drives HCC progression remain to be fully elucidated. In this study, we identified nuclear prelamin A recognition factor (NARF) as a novel matrix stiffness-responsive gene, whose transcription is directly regulated by the mechanosensor Yes-associated protein (YAP). Clinically, NARF exhibited high expressions in HCC tissues, and its overexpression was closely correlated with poor prognostic outcomes in HCC patients. Functionally, NARF knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, whereas NARF overexpression enhanced these cellular processes. NARF silencing attenuated HCC cell growth and lung metastasis in vivo. RNA-sequencing analysis revealed a strong correlation of NARF with Wnt signaling activation. Further experiments confirmed that NARF positively regulated the expression of key Wnt target genes (MYC, CCND1, SNAIL, and TWIST1) in HCC cells. Mechanistically, NARF recruited acetyltransferase EP300 to enhance H3K27 acetylation at lymphoid enhancer binding factor 1 (LEF1)-binding sites, thereby amplifying LEF1-dependent transcriptional activity. LEF1 knockdown markedly abrogated NARF-mediated oncogenic activity in vitro and in vivo, confirming LEF1 as a critical downstream effector of NARF. Collectively, our findings identify NARF as stiffness-responsive driver that is transcriptionally regulated by YAP protein in HCC. By activating LEF1-mediated Wnt signaling in an EP300 dependent manner, NARF promotes HCC growth and metastasis, highlighting its potential as a prognostic biomarker and therapeutic target for HCC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120122"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-mediated modulation of tumor angiogenesis: From proangiogenic mediators to extracellular vesicles","authors":"Weronika Jurczyk ,&nbsp;Jadwiga Jablonska ,&nbsp;Mateusz Smolarz","doi":"10.1016/j.bbamcr.2026.120126","DOIUrl":"10.1016/j.bbamcr.2026.120126","url":null,"abstract":"<div><div>Angiogenesis is a tightly controlled physiological process that enables the formation of new blood vessels. Under normal conditions, it is regulated by a balance between pro- and anti-angiogenic signals. In cancer, this equilibrium is disrupted, and angiogenesis becomes a pathological mechanism that supports tumor growth, progression, and metastasis. The process is orchestrated by a variety of cells, including endothelial cells (EC), fibroblasts, macrophages, platelets, neutrophils, and cancer cells, which release chemical mediators. Among them, growth factors such as VEGF, FGF, PDGF, angiopoietins, and TGF-β play a central role by activating signaling pathways that stimulate endothelial proliferation, migration, survival, and extracellular matrix (ECM) remodeling. Their activity drives the “angiogenic switch,” a hallmark of early tumor development. Neutrophils, the most abundant immune cells in circulation, exert a dual influence on this process. Pro-tumor neutrophils enhance angiogenesis through the secretion of VEGF-A, TGF-β, MMP-9, IL-8, and the release of neutrophil extracellular traps, facilitating vascular permeability and tumor progression. Conversely, anti-tumor neutrophils release TNF-α, IL-12, and chemokines such as CXCL9/10, which inhibit angiogenesis and restrain tumor expansion. Recently, small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication. Neutrophil-derived sEVs transport proangiogenic miRNAs, proteins, and signaling molecules that influence endothelial activation, epithelial-to-mesenchymal transition, therapy resistance, and metastatic potential. Given their unique molecular cargo, they represent potential modulators of tumor angiogenesis, although studies in this area remain limited. This review summarizes the principal mechanisms of angiogenesis, the multifaceted role of neutrophils in shaping tumor vasculature, and the emerging contribution of neutrophil-derived sEVs.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120126"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147301605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP49 regulates lipid metabolism in hepatocellular carcinoma by stabilizing RACK1 to promote tumor proliferation and migration","authors":"Weikang Xu ,&nbsp;Jijun Shan ,&nbsp;Jifei Wang ,&nbsp;Yudi Zhou ,&nbsp;Yiming Ouyang ,&nbsp;Yananlan Chen ,&nbsp;Qiyang Zhou","doi":"10.1016/j.bbamcr.2026.120107","DOIUrl":"10.1016/j.bbamcr.2026.120107","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While ubiquitin-specific peptidase 49 (USP49) has been implicated in various cancers, its role in HCC is unclear. Here, we found that USP49 is upregulated in HCC tissues and associated with poor prognosis. Functional assays demonstrated that USP49 promotes HCC proliferation and migration both in vitro and in vivo. Mechanistically, USP49 directly interacts with and deubiquitinates RACK1, thereby stabilizing it. This stabilization leads to RACK1-driven transcriptional activation of key fatty acid metabolic enzymes, enhancing triglyceride synthesis and fueling tumor growth through metabolic reprogramming. Collectively, our study identifies the USP49/RACK1 axis as a critical driver of HCC progression and nominates USP49 as a promising therapeutic target.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120107"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATM kinase phosphorylates HSP90 on T297 changing its conformation dynamics and promoting its interaction with HER2 receptor tyrosine kinase","authors":"Giulia Fianco ,&nbsp;Irene Taddei ,&nbsp;Veronica Oropallo ,&nbsp;Claudia Contadini ,&nbsp;Alessandra Ferri ,&nbsp;Laura Coculo ,&nbsp;Stefano A. Serapian ,&nbsp;Giorgio Colombo ,&nbsp;Venturina Stagni ,&nbsp;Daniela Barilà","doi":"10.1016/j.bbamcr.2026.120110","DOIUrl":"10.1016/j.bbamcr.2026.120110","url":null,"abstract":"<div><div>Heat Shock Protein 90 (HSP90) is an essential molecular chaperone whose activity is regulated not only by co-chaperones but also by distinct post-translational modifications. Interestingly, its chaperone activity is essential for the stability of several oncogenes, among which the receptor tyrosine kinase HER2. HER2 is overexpressed in 20–30% of breast and ovarian cancers. Its overexpression triggers proliferative and transforming pathways aberrant activation and therefore frequently correlates with invasive and poor prognostic features, and associates with shorter patient survival. Of note, HSP90 inhibitors have been studied in HER2-positive breast cancer and have shown promising results. Unexpectedly, we previously reported that ATM promotes the interaction of HER2 with HSP90 therefore sustaining HER2 protein stability and tumorigenicity.</div><div>To further investigate the interplay between HER2-HSP90 and ATM, we tested the hypothesis that ATM could phosphorylate HSP90. We confirmed that ATM activation can induce the phosphorylation of HSP90 in HER2 positive breast cancer models. Point mutagenesis showed that T297 is the major site targeted by ATM kinase and importantly the unphosphorylatable mutant HSP90-T297A displays a reduced ability to interact with HER2, and to prevent its ubiquitination and degradation. Consistently, the overexpression of HSP90-T297A impinges on the viability of HER2-overexpressing cells, further supporting a role of this phosphorylation in the modulation of HER2 tumorigenicity. T297 is located in the middle domain of HSP90, a region that is involved in the interaction of HSP90 with clients. Consistently, structural studies indicate that T297 phosphorylation can indeed favor the chaperone's interaction with HER2, further supporting our hypothesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120110"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NSUN2 activated by KLF6 can mediate m5C modification of NCOA4 to enhance ferroptosis of OGD/R-induced SH-SY5Y cells in ischemic stroke","authors":"Genshan Gao ,&nbsp;Yue Xu ,&nbsp;Yao Liu,&nbsp;Shuqing Meng,&nbsp;Nannuan Liu","doi":"10.1016/j.bbamcr.2025.120102","DOIUrl":"10.1016/j.bbamcr.2025.120102","url":null,"abstract":"<div><div>Ischemic stroke (IS) constitutes the majority of stroke cases. Ferroptosis, a non-apoptotic form of programmed cell death, is an essential mechanism of IS. This study aimed to investigate a ferroptosis-related molecular mechanism in IS progression. IS model in vitro was induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells. RT-qPCR and Western blotting were performed for detection of NOP2/Sun RNA methyltransferase family member 2 (NSUN2), nuclear receptor coactivator 4 (NCOA4), and Krueppel-like factor 6 (KLF6). Cell functions were assessed by MTT assay, flow cytometry, and enzyme-linked immunosorbent assay. Mitochondrial membrane potential and other ferroptosis indicators were examined using kits. Molecular binding was detected using methylated RNA immunoprecipitation (MeRIP), RIP, dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. IS animal model was established by middle cerebral artery occlusion (MCAO). OGD/R-induced apoptosis, inflammation, and ferroptosis of SH-SY5Y cells were suppressed by NCOA4 knockdown. NSUN2 could promote NCOA4 mRNA stability by mediating 5-methylcytosine (m5C) methylation modification of NCOA4, and YBX1 served as a reader protein. NSUN2 contributed to OGD/R-induced SH-SY5Y cell injury via upregulating NCOA4. KLF6 acted as a transcription factor to activate NSUN2 transcription, and then facilitated nerve injury of OGD/R-induced SH-SY5Y cells. Animal assay showed that silencing NSUN2 inhibited infarct volume, tissue injury, neurological function, and neuroinflammation in MCAO rats. These current findings affirmed that KLF6-activated NSUN2 could contribute to ferroptosis of OGD/R-induced SH-SY5Y cells via inducing NCOA4 m5C modification, providing a novel insight into the mechanism of ferroptosis in IS.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120102"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}