Cellular & Molecular Biology Letters最新文献

{"title":"TCRζ-driven pre-signaling organization of Lck in Rab11⁺ endosomes shapes TCR activation.","authors":"Konstantina Karpouzou, Nikolaos Koutras, Ioannis Tyritidis, Evangelos Tsioupros, Andriana G Kotini, Vassilis Roukos, Konstantina Nika","doi":"10.1186/s11658-026-00993-x","DOIUrl":"10.1186/s11658-026-00993-x","url":null,"abstract":"<p><strong>Background: </strong>T cell activation relies on the precise spatiotemporal regulation of T cell receptor (TCR) signaling at the immunological synapse, where vesicular trafficking coordinates the delivery of key signaling molecules. Endosomal pools of lymphocyte-specific protein tyrosine kinase (Lck) and its immediate substrate, the TCRζ chain, have been linked to TCR signaling competence, yet the mechanisms that regulate and coordinate their trafficking routes remain unresolved.</p><p><strong>Methods: </strong>We simultaneously tracked the endosomal localization dynamics of endogenous Lck, ζ chain, and the TCR in unperturbed cells and under conditions that preserve the endosomal network integrity. Genetic modifications, confocal microscopy, quantitative phospho-flow analysis, and biochemical assays were used to map trafficking behaviors and signaling outputs. Datasets were analyzed using unpaired Student's t-tests.</p><p><strong>Results: </strong>We identified a previously unrecognized plasma membrane-resident pool of ζ that exists independently of the TCR complex yet remains competent for phosphorylation and ZAP-70 recruitment. This \"standalone\" ζ population orchestrates the mobilization of Lck and CD45 into Rab11-positive compartments, establishing pre-assembled, signaling-primed platforms prior to synapse formation. These structures can accommodate constitutively phosphorylated ζ and ζ-chain-associated protein kinase 70 (ZAP-70), which depend on the presence of endosomal Lck.</p><p><strong>Conclusions: </strong>This work uncovers a mechanistic link between vesicular ζ and Lck pools and establishes their coordinated trafficking as a key determinant of TCR activation. Our findings indicate that vesicular preprimed assemblies can provide a reservoir of signaling mediators, serving to sustain TCR signaling without a requirement for continuous receptor engagement, thereby determining the threshold, sensitivity, and persistence of T cell responses. By revealing a TCR-uncoupled ζ population that seeds endosomal signaling platforms, our study advances current models of T cell activation and highlights an additional layer of regulation in proximal signaling events. These insights also have translational implications, particularly within the context of improving the efficiency, performance, and safety of T cell immunotherapies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the structure of swine leukocyte antigen class I molecules.","authors":"Yong-Yu Gao, Hai-Yang Li, Si-Yu Yang, Chen-Jun Sang, Yu-Die Cao, Yue Tang, Zi-Bin Li, Gui-Xue Hu, Feng-Shan Gao","doi":"10.1186/s11658-026-00990-0","DOIUrl":"10.1186/s11658-026-00990-0","url":null,"abstract":"<p><p>Swine leukocyte antigen class I (SLA-I) molecules are swine orthologs of human MHC class I molecules and are encoded by three classical loci, SLA-1, SLA-2, and SLA-3. By engaging T-cell receptors (TCRs), these cell-surface proteins present antigenic peptides, whose binding specificity is largely dictated by the architecture of the peptide-binding groove (PBG) and its constituent pockets. Although early SLA-I research primarily emphasized molecular and functional features, recent advances in structural biology have yielded an increasing number of crystal structures of SLA-I-peptide complexes, providing critical insights into the principles of peptide presentation and T-cell recognition in pigs. In this review, we examine the structural features of SLA-I molecules, focusing on the PBG and binding pockets that accommodate peptide anchor residues. Structural studies revealed that the SLA-I PBG, while architecturally conserved, exhibits pronounced allelic polymorphism and plasticity, predominantly within its six binding pockets (A-F). A key insight is the profound functional impact of micropolymorphisms; for instance, single-residue variations in pockets such as D can dramatically alter the peptide-binding specificity and repertoire. Finally, we highlight current knowledge gaps and future research directions to facilitate the exploitation of SLA-I structural features for targeted vaccine design and immunotherapeutic development, thus addressing the challenges of porcine immune recognition.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-GlcNAc transferase governs spermatogenic mitotic-to-meiotic transition and progression by coordinating transcription and alternative splicing programs.","authors":"Zhiming Ding, Caiyun Wu, Min Li, Kaiqin Hu, Xuanxi Li, Zhen Chen, Kuokuo Li, Huiru Cheng, Qunshan Shen, Yunxia Cao, Huifen Xiang, Rui Guo","doi":"10.1186/s11658-026-00972-2","DOIUrl":"10.1186/s11658-026-00972-2","url":null,"abstract":"<p><strong>Background: </strong>O-GlcNAcylation is a post-translational modification (PTM) uniquely catalyzed by O-GlcNAc transferase (OGT), which has been linked to tumorigenesis and neurodegeneration. However, its roles in mammalian spermatogenesis remain unexplored. This study aims to elucidate the functional mechanisms of OGT in spermatogenesis and male fertility.</p><p><strong>Methods: </strong>We employed immunoprecipitation-mass spectrometry (IP-MS) to identify candidate O-GlcNAcylated substrates of OGT in juvenile mouse testes. To explore the physiological roles of OGT and O-GlcNAcylation, we constructed a mouse model with postnatal germ cell-specific deletion of Ogt via Stra8-Cre. In addition, we performed integrated bulk and single-cell RNA sequencing analyses to investigate the potential mechanisms by which OGT and O-GlcNAcylation deficiency impairs spermatogenesis.</p><p><strong>Results: </strong>The results showed stage-specific OGT enrichment and O-GlcNAcylation in mouse testicular spermatogonia and early spermatocytes. Furthermore, OGT was found to interact with and O-GlcNAcylate transcription factors (e.g., HCFC1) as well as splicing regulators (e.g., SRSF1 and SF3B3) in mouse testes. Postnatal germ cell-specific Ogt deletion impaired spermatogonial differentiation, disrupted meiotic initiation and progression, and induced apoptosis, ultimately leading to male infertility. Mechanistically, Bulk RNA sequencing (RNA-seq) analysis revealed that OGT deficiency dysregulated transcriptional and alternative splicing programs, affecting genes critical for the mitotic-meiotic transition (e.g., Ythdc2 and Rbm46) and meiotic progression (e.g., Stra8, Stag3, and Syce2) in the testes. Single-cell RNA sequencing further uncovered aberrant retention of mitotic transcripts (e.g., Ccna2 and Ccnb1) in spermatocytes and impaired mRNA metabolism during spermatogonial differentiation. In addition, OGT deficiency caused cytoplasmic mislocalization and reduced expression of core transcription factors and splicing regulators in spermatocytes.</p><p><strong>Conclusions: </strong>These findings establish that OGT and its mediated O-GlcNAcylation coordinate essential gene expression and mRNA metabolism during mitotic-to-meiotic transition and meiotic progression. Moreover, our study provides mechanistic insights into the pathogenesis of male infertility associated with O-GlcNAcylation dysregulation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactobacillus acidophilus abolishes oxalate-mediated renal epithelial barrier disruption and calcium oxalate monohydrate crystal adhesion to renal epithelial cells.","authors":"Anantaya Putpim, Chadanat Noonin, Paranyu Chawanpaiboon, Onnipa Pawano, Somsakul Phuangkham, Paleerath Peerapen, Visith Thongboonkerd","doi":"10.1186/s11658-026-00985-x","DOIUrl":"10.1186/s11658-026-00985-x","url":null,"abstract":"<p><strong>Background: </strong>It is generally known that kidney stone disease (KSD) is associated with alterations in urinary microbiome, but the roles of the urinary microbiome in KSD pathogenesis remain unclear.</p><p><strong>Methods: </strong>This study addressed the impact of Lactobacillus acidophilus (a commensal bacterium found in normal urine) on renal epithelial integrity, calcium oxalate monohydrate (COM) crystal-cell adhesion, expression of membrane receptors of COM crystals, and oxalate degradation under oxalate-induced stress (a known inducer of KSD). Inner medullary collecting duct cells (mIMCD-3) were cultured for 24 h under control or oxalate-induced (by 0.6 mM sodium oxalate; NaOx) conditions without or with L. acidophilus (at 1 × 10³ colony-forming unit (CFU)/ml) co-incubation.</p><p><strong>Results: </strong>NaOx reduced transepithelial resistance (TER) of the mIMCD-3 monolayer and downregulated ZO-1, a tight junction (TJ) protein. Additionally, NaOx enhanced the COM crystal-binding capability of mIMCD-3 cells by upregulating a COM crystal receptor, annexin A2, on cell membranes. Such harmful effects of NaOx were abolished when mIMCD-3 cells were co-cultured with L. acidophilus. Moreover, culturing L. acidophilus in artificial urine (AU) supplemented with NaOx for 24 h revealed that the oxalate level in AU decreased, suggesting the oxalate-degrading activity of the bacterium in an AU environment.</p><p><strong>Conclusions: </strong>L. acidophilus prevented oxalate-mediated renal epithelial barrier disruption and COM crystal adhesion to renal epithelial cells by preserving ZO-1 and annexin A2 expression at their basal levels, at least in part, via its oxalate-degrading property.</p><p><strong>Clinical trial number: </strong>Not applicable (This is not a clinical trial).</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenin alleviates lipotoxicity-induced impairment of skin wound healing.","authors":"Min Fu, Yi Wang, Chunyi Wu, Xiaoyu Deng, Zaiyong Zheng, Yang Yu, Yajun Yu, Lunkun Ma, Jianguo Feng, Chunxiang Zhang","doi":"10.1186/s11658-026-00970-4","DOIUrl":"10.1186/s11658-026-00970-4","url":null,"abstract":"<p><p>Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic stress has been unknown. Here, we demonstrate for the first time that Angiogenin effectively protects against lipotoxicity-induced delayed skin repair. In a cellular lipotoxicity model induced by oleic and palmitic acids (OPA) using human umbilical vein endothelial cells (HUVECs), the levels of Angiogenin decreased in a time- and dose-dependent manner. Meanwhile, a similar reduction was also observed in the skin tissue of high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE)^-/- mice. Restoring Angiogenin levels significantly enhanced endothelial proliferation, migration, and angiogenesis, rescuing OPA-induced impairment. Through RNA-seq and subsequent validations, we provide novel mechanistic insight into Angiogenin's protective action: Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. Critically, we show that the Angiogenin-mediated endothelial rescue is strictly dependent on this Cav1 upregulation. Furthermore, topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE^-/- and high-fat diet/STZ-induced diabetic mice. Collectively, our study unveils a novel Angiogenin-Cav1 axis in endothelial protection, positioning Angiogenin as a promising therapeutic candidate for lipotoxicity-induced impairment of skin wound healing.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SLK protects against cerebral ischemia-reperfusion injury by regulating USP8-mediated HIF-1α stabilization and RhoA/ROCK activation.","authors":"Yuetao Wen, Zhiyu Xiong, Zhiyuan Wang, Ya He, You Wang, Yuan Tao, Liping Huang, Chen Gong, Shuyu Jiang, Guo Du, Yangmei Chen, Tao Xu","doi":"10.1186/s11658-026-00988-8","DOIUrl":"10.1186/s11658-026-00988-8","url":null,"abstract":"<p><strong>Introduction: </strong>Acute ischemic stroke (AIS) represents a major global contributor to mortality and chronic disability, with few effective therapeutic targets available. Identifying druggable genes associated with AIS is therefore critical for developing novel interventions.</p><p><strong>Methods: </strong>A comprehensive approach combining Mendelian randomization, multi-omics integration, and machine learning was employed to identify candidate druggable genes. Causal relationships were confirmed through genetic colocalization, and candidate genes were further validated in a retrospective clinical cohort comprising 60 patients who experienced AIS and 30 healthy controls. Functional and mechanistic investigations were performed using a male mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, oxygen-glucose deprivation/reperfusion (OGD/R) in HT22 cells, and 293 T cells.</p><p><strong>Results: </strong>SLK emerged as a genetically causal AIS gene and a central component of the optimal predictive model. Plasma SLK levels were elevated in patients who experienced AIS, demonstrating strong diagnostic and prognostic value and serving as an independent predictor of unfavorable 3-month outcomes after adjusting for age, sex, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Knockdown of SLK conferred neuroprotection both in vivo and in vitro. SLK interacted with and phosphorylated the deubiquitinase USP8, increasing its activity and suppressing K48-linked polyubiquitination and degradation of HIF-1α. HIF-1α was stabilized following activation of the RhoA/ROCK signaling pathway, aggravating ischemic injury, whereas USP8 overexpression mitigated the neuroprotective effects of SLK knockdown.</p><p><strong>Conclusions: </strong>These findings identify SLK as a neuron-specific proischemic factor and a potential therapeutic target, elucidate the SLK-USP8-HIF-1α-RhoA/ROCK pathway as a key mechanistic pathway, and highlight plasma SLK as a promising diagnostic and prognostic biomarker with translational relevance.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Targeting fibroblast activation protein-α to treat renal fibrosis.","authors":"Li Gong, Xinyu Lu, Na Ma, Tao Lu, Yuhong Gong, Liwei Hao, Weikang Xu, Qianbing Zhang, Xiaolan Chen, Qinglin Mo, Jiexing Tan, Henrique de Paula Lemos, Alexander Speechley, Wenwei Tu, Jianpiao Cai, Lei Huang, Wei Zhu, Sha Wu","doi":"10.1186/s11658-026-00967-z","DOIUrl":"10.1186/s11658-026-00967-z","url":null,"abstract":"","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy.","authors":"Wenlong Zhu, Yanjie Zhang, Runze Jiang, Li Wang, Jin Ding","doi":"10.1186/s11658-026-00979-9","DOIUrl":"10.1186/s11658-026-00979-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics of its tissue structure, HCC has a high propensity for metastasis. Unfortunately, most patients are diagnosed at the middle or advanced stage and present with metastasis. The occurrence of metastasis often indicates a severe deterioration of the condition and the loss of an opportunity for radical treatment. Thus, immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the first-line treatment for patients with advanced metastasis. The tumor immune microenvironment (TIME), as the core immune component within tumors, has been confirmed to be significantly associated with metastasis through the complex crosstalk with suppressive immune cells. This crosstalk dynamically participates in the metastatic cascade of HCC, assisting tumors in completing invasion and diffusion. The goal of immunotherapy is to restore the function of exhausted immune cells in the TIME. However, the complex immunosuppressive microenvironment often weakens treatment responses, posing severe challenges to the application of immunotherapies. Accordingly, there is an urgent need to deeply investigate the crosstalk among diverse cell types within the immunosuppressive microenvironment and to systematically elucidate the impact of such intercellular crosstalk on the HCC metastasis as well as the response to immunotherapy, so as to improve the clinical benefit rate of immunotherapy for patients with metastatic HCC. This review focuses on the dual role of immune cells in HCC metastasis and the novel mechanisms by which they promote the HCC metastatic cascade. It systematically summarizes current therapeutic strategies targeting the immunosuppressive microenvironment to combat HCC metastasis. On this basis, it prospectively proposes the future development direction of immunotherapy, providing more effective guidance for the clinical diagnosis and treatment of patients with metastatic HCC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.","authors":"Renjie Xie, Ruixue Geng, Yuchen Wang, Chenyue Zhan, Xinyue Deng, Yanting Duan, Juyong Liang, Jiafeng Wang, Ruimin Liang, Jingyan Ge, Minghua Ge, Xiaozheng Zhu","doi":"10.1186/s11658-026-00973-1","DOIUrl":"10.1186/s11658-026-00973-1","url":null,"abstract":"<p><strong>Background: </strong>Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes.</p><p><strong>Methods: </strong>In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8⁺ T-cell infiltration and cytokine secretion.</p><p><strong>Results: </strong>This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sperm surface protein disulfide isomerase ERp57 is crucial for mammalian fertilization but functions independently of IZUMO1.","authors":"Emily Forster, Sophie Dupuis, Côme Ialy-Radio, Vitor Hugo B Serrão, Patrick Yip, Marine Foritano, Sandrine Barbaux, Jeffrey E Lee, Ahmed Ziyyat","doi":"10.1186/s11658-026-00984-y","DOIUrl":"10.1186/s11658-026-00984-y","url":null,"abstract":"<p><strong>Background: </strong>Human fertilization requires fusion of spermatozoon and oocyte membranes to form a diploid zygote, beginning with adhesion mediated by spermatozoon IZUMO1 and oocyte JUNO. Current models propose that IZUMO1 dimerizes after interacting with JUNO, possibly triggered by a protein disulfide isomerase. It has been proposed that protein disulfide isomerase ERp57 is the trigger for IZUMO1 dimerization, a mechanism supported by parallels in viral entry, but direct evidence is lacking.</p><p><strong>Methods: </strong>In vitro fertilization studies were performed for both mice and humans using ERp57 inhibitors to confirm the importance of ERp57 in mammalian fertilization. Additionally, for this study, we generated a sperm-specific ERp57 conditional knockout mouse model and performed in vivo and in vitro fertilization experiments. Biophysical assays, including dynamic light scattering and a fluorescence-based dissociation assay, were developed and utilized to investigate interactions between ERp57 and IZUMO1. Structural modeling was used to supplement the ERp57 and IZUMO1 interaction findings.</p><p><strong>Results: </strong>Here, we reveal that ERp57 is crucial for mammalian fertilization but does not show evidence of any direct interaction with IZUMO1. ERp57 inhibition significantly reduces fertilization in human and mouse in vitro assays, and ERp57 spermatozoa conditional knockout (scKO) males exhibit severe hypofertility in vivo and in vitro. ERp57 localizes to the equatorial segment of human spermatozoa following the acrosome reaction, consistent with a role in gamete interaction. However, ERp57-deficient spermatozoa fail to accumulate in the perivitelline space, pointing to a role upstream of membrane fusion. Additionally, ERp57 neither promotes IZUMO1 dimerization nor facilitates dissociation of the IZUMO1-JUNO complex. Structural modeling predicted no significant interaction between ERp57 and IZUMO1, supporting experimental findings.</p><p><strong>Conclusions: </strong>These findings establish ERp57 as critical for mammalian fertilization but challenge existing assumptions about its mechanistic involvement in gamete membrane fusion. Our research contributions provide key new mechanistic insights that reexamine and reshape the current paradigms surrounding the fundamental process of sperm-egg fusion. By addressing a long-standing bottleneck in the field, our work opens new avenues of investigation that could finally lead to the identification of the elusive human sperm-egg fusogen.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}