Cellular & Molecular Biology Letters最新文献

{"title":"Genomic context of mutations in MIR142 in blood cancers: summary and integrative analysis.","authors":"Wladyslaw Wegorek, Adrian Tire, Daniel Kuznicki, Julia Richter, Maciej Giefing, Wolfram Klapper, Piotr Kozlowski, Paulina Galka-Marciniak","doi":"10.1186/s11658-026-00933-9","DOIUrl":"10.1186/s11658-026-00933-9","url":null,"abstract":"<p><p>MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells and plays an essential role in the development, differentiation, and maturation of various lymphopoietic and hematopoietic lineages. To gain a deeper understanding of MIR142 mutations, we summarize all data on these mutations, including their frequency in different cancers, their location within the miR-142 precursor, and their functional consequences. We also analyzed MIR142 mutations within a broader genomic context in thousands of cancers, including hundreds of blood neoplasms. Our results show that the most prevalent mutations in the MIR142 gene originate from a clearly distinct hotspot in hematologic malignancies, concentrated mainly within the sequence of the secondary miR-142 precursor. We found substantial differences in mutation frequency and distribution across cancer types. This indicates that MIR142 alterations are not random consequences of an increased mutational load but are likely subject to positive selection, underscoring their biological and clinical significance.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970700","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":"m⁶A-modificated Linc00707 promotes the progression of TNBC via U2AF2-mediated alternative splicing of ATG4B.","authors":"Hongli Li, Yong Li, Qinghua Liu, Chonggao Yin, Yunxiang Zhang, Peng Gao","doi":"10.1186/s11658-026-00937-5","DOIUrl":"10.1186/s11658-026-00937-5","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) represents a clinically aggressive breast cancer subtype with limited therapeutic options. Emerging evidence suggests that long intergenic noncoding RNA 00707 (Linc00707) plays a role in TNBC; however, the upstream regulators governing Linc00707 expression and the mechanisms by which it contributes to tumor progression remain largely undefined.</p><p><strong>Method: </strong>The FOXP3-mediated transcriptional regulation of Linc00707 was analyzed using chromatin immunoprecipitation and luciferase reporter assays. The post-transcriptional regulation of Linc00707 was examined by RNA immunoprecipitation (RIP), methylated RIP, and RNA pull-down assays to assess WTAP-dependent m⁶A modification, IGF2BP2-mediated stabilization, and U2AF2 interaction. RNA sequencing and biochemical analyses were used to identify downstream regulatory pathways. The binding of oligo-anti-Linc00707 to Linc00707 and its ability to disrupt U2AF2 association were confirmed by RIP and RNA fluorescence in situ hybridization (RNA-FISH). Cellular assays and nude mouse xenograft models were employed to evaluate functional and therapeutic effects.</p><p><strong>Results: </strong>FOXP3 was found to transcriptionally activate Linc00707 through direct promoter binding. The WTAP-mediated m⁶A modification enhanced the IGF2BP2-dependent stabilization of Linc00707. In the nucleus, Linc00707 interacted with the splicing factor U2AF2, with nucleotides 1-593 identified as a critical interaction region. Building on this observation, we further showed that the Linc00707-U2AF2 interaction functionally controls U2AF2 expression and stability via FOXP3. The Linc00707-U2AF2 complex was associated with altered alternative splicing of the autophagy-related gene ATG4B, contributing to enhanced TNBC cell proliferation, invasion, and autophagy suppression. Importantly, oligonucleotides complementary to the U2AF2-binding region of Linc00707 (oligo-anti-Linc00707) disrupted this interaction, attenuated Linc00707-driven oncogenic phenotypes, and restored autophagic activity. In vivo, oligo-anti-Linc00707 treatment significantly reduced tumor growth, supporting its therapeutic potential in TNBC.</p><p><strong>Conclusions: </strong>FOXP3 activates Linc00707 transcription in TNBC. WTAP-mediated m⁶A modification enhances Linc00707 stability via IGF2BP2. Linc00707 recruits U2AF2 to drive oncogenic ATG4B splicing, promoting tumor progression. Oligo-anti-Linc00707 specifically blocks Linc00707-U2AF2 complex formation, reversing its tumor-promoting and autophagy-suppressing functions. Thus, targeting Linc00707 represents a promising therapeutic strategy for TNBC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970750","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":"Discovery of a novel cannabidiol-derived transient receptor potential vanilloid 4 inhibitor to reduce pulmonary edema and lung vascular permeability in mice.","authors":"Yassir Arfath, Pankaj Singh Cham, Tusharika Kotra, Rahila Akhter, Sumeer Ahmed, Mandeep Kour, Sheikh Tasduq Abdullah, Parvinder Pal Singh, Sheikh Rayees, Zabeer Ahmed","doi":"10.1186/s11658-026-00939-3","DOIUrl":"10.1186/s11658-026-00939-3","url":null,"abstract":"<p><strong>Introduction: </strong>Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective benefits, reducing vascular leakage, enhancing blood oxygenation, and alleviating edema.</p><p><strong>Objectives: </strong>We designed, synthesized, and preclinically evaluated cannabidiol-derived TRPV4 channel inhibitors for potential therapeutic application in ALI and future clinical translation.</p><p><strong>Methods: </strong>We identified a lead cannabidiol-derived TRPV4 inhibitor through specific in vitro screening assays. The lead compound was then tested in a series of animal models of ALI. Initial evaluation employed the lipopolysaccharide (LPS) induced lung injury model, followed by models involving TRPV4 overexpression in alveolar macrophages, as well as models featuring TRPV4 hyperactivation. These models were strategically chosen to replicate key pathological features of clinical ALI.</p><p><strong>Results: </strong>Our investigation revealed that administration of the lead derivative CS-85(4j) demonstrated significant protective effects in a mouse model of ALI. CS-85 effectively prevented lung edema and maintained the integrity of pulmonary vascular barrier. Notably, it inhibited neutrophil influx into the lung, reduced proinflammatory cytokine production, and mitigated associated pathological changes. In additional relevant preclinical in vivo models, we further investigated how TRPV4 hyperactivation via pharmacological stimulation and overexpression in alveolar macrophages through liposome-mediated gene delivery exacerbated key features of ALI. CS-85 effectively reduced this exaggerated lung inflammation and alleviated the ALI features. In exploring the downstream mechanisms of CS-85, we found that its pharmacological efficacy is mediated through modulation of the NLRP3-caspase-1, NFAT, and NF-ĸB signaling pathways, all of which are crucial inflammatory cascades.</p><p><strong>Conclusions: </strong>We identified CS-85 as a potent and promising TRPV4 inhibitor that demonstrates strong preclinical efficacy in mitigating ALI by preserving vascular integrity and modulating key inflammatory signaling pathways. Its dual mechanism of action highlights its therapeutic potential for ALI and supports further clinical evaluation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962380","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":"QSOX1 confers ferroptosis resistance via redox modification of SLC7A11 in colorectal cancer.","authors":"Mengqi Jia, Hanxiang Chen, Yulin Liu, Jianzhuang Guo, Xiaofei Wang, Qiang Liu, Zhiheng Liu, Zhaoqing Meng, Chunqing Wang, Yunqiu Wang","doi":"10.1186/s11658-026-00938-4","DOIUrl":"10.1186/s11658-026-00938-4","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer.</p><p><strong>Methods: </strong>We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe²⁺, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers.</p><p><strong>Results: </strong>QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis.</p><p><strong>Conclusions: </strong>QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1-SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947715","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":"Implications of ferritinophagy in cardiovascular diseases and its pharmacological modulation: underlying mechanisms and clinical translation strategies.","authors":"Yan-Lin Wu, Ling Xiao, He-Ning Li, Lin-Xi Chen","doi":"10.1186/s11658-026-00941-9","DOIUrl":"10.1186/s11658-026-00941-9","url":null,"abstract":"<p><p>Ferritinophagy is a crucial intracellular process mediated by the selective autophagy receptor nuclear receptor coactivator 4 (NCOA4), which plays a central role in maintaining iron homeostasis by regulating ferritin degradation. In recent years, its function as a key interface between autophagy and iron metabolism has attracted considerable attention owing to its pathophysiological relevance in cardiovascular diseases (CVDs). This review systematically delineates the molecular mechanisms of ferritinophagy, including the formation of the NCOA4-ferritin complex, lysosomal degradation pathways, and the multilayered regulatory networks involved. Particular focus is given to the dual role of ferritinophagy in cardiovascular pathology, encompassing myocardial ischemia-reperfusion injury (MIRI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM). While moderate ferritinophagy activity is essential for maintaining adequate cardiac iron supply, its excessive activation leads to labile iron accumulation, oxidative stress via the Fenton reaction, and ferroptosis, thereby exacerbating myocardial injury and pathological remodeling. Consequently, this article provides a comprehensive overview of pharmacological strategies targeting ferritinophagy, including direct inhibition approaches (e.g., NCOA4 small interfering RNA (siRNA) and lysosomal inhibitors) and indirect modulation strategies (e.g., ferroptosis inhibitors and natural compounds). Finally, challenges to clinical translation are addressed, particularly regarding tissue specificity, drug delivery efficiency, and long-term safety. Future research directions are proposed, including the development of organ-specific targeting strategies and the exploration of combination therapies, with the aim of offering novel insights and potential therapeutic avenues for the prevention and treatment of CVDs.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927064","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":"Coming to light: the transcriptional regulatory roles of histone lysine crotonylation in health and disease.","authors":"Shang-Kun Dai, Naixia Ren, Chang-Mei Liu, Fengtang Yang","doi":"10.1186/s11658-026-00935-7","DOIUrl":"10.1186/s11658-026-00935-7","url":null,"abstract":"<p><p>Research on histone lysine crotonylation has evolved from identifying its core regulatory factors and mapping its genome-wide landscape to dissecting its functions in physiological and pathological contexts. Since its discovery nearly 15 years ago, extensive biochemical, structural, and genetic studies have deepened our understanding of how this evolutionarily conserved modification is integrated into intricate epigenetic regulatory networks. In this review, we first summarize mechanistic insights into the molecular basis of transcriptional regulation mediated by histone crotonylation, and discuss competitive crosstalk between this modification and histone acetylation in local chromatin regions. We then present an updated integrative framework to systematically delineate the regulatory roles of histone crotonylation across genes with distinct transcriptional states, as well as its functional implications in health and disease. Finally, we propose a unifying context-dependent model for histone crotonylation-mediated transcriptional regulation, and outline key challenges and future directions in the field.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926995","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":"H₂S induces apoptosis of tumors with high IDO1 expression via NR4A1-BCL-2 and SOCS3 pathways.","authors":"Zhen Ning Tony He, Fangzhou Meng, Xiaoyang Qian, Yuying Liu, Xin Fang, Dan Yang, Qing Yang","doi":"10.1186/s11658-026-00945-5","DOIUrl":"10.1186/s11658-026-00945-5","url":null,"abstract":"<p><strong>Background: </strong>Hydrogen sulfide (H₂S) has been reported to exert both protumor and antitumor functions. It is worthy to clarify the condition under which H₂S exerts antitumor effects and its underlying mechanism. Our previous study connected the immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1) and H₂S by revealing that H₂S downregulates IDO1 expression, leading to our hypothesis that antitumor effect of H₂S is associated with IDO1 expression in tumor cells.</p><p><strong>Methods: </strong>Apoptosis, cellular distribution of NR4A1, phosphorylation of IDO1, and the binding of phosphorylated IDO1 and SOCS3 are examined both in vitro and in vivo.</p><p><strong>Results: </strong>In this study, we confirm our hypothesis by showing that H₂S significantly reduces proliferation and induces apoptosis of tumor cells with high IDO1 expression. In tumor cells with high IDO1 expression, H₂S promotes the translocation of NR4A1 out of nucleus and its binding with BCL-2, as well as the phosphorylation of IDO1 and the codegradation of phosphorylated IDO1 and SOCS3. Such mechanism by which H₂S induces apoptosis of tumors with high IDO1 expression is also elucidated in tumor-bearing mice, where H₂S shows great therapeutic effect against tumors with high IDO1 expression.</p><p><strong>Conclusions: </strong>H₂S induces apoptosis of tumor cells with high expression of IDO1 by promoting NR4A1-BCL-2 apoptotic pathway and the codegradation of phosphorylated IDO1 and SOCS3. Our study provides new theoretical and experimental evidence for a strategy for tumor therapy with H₂S.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927004","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":"NAT10-mediated ac⁴C modification of TNFRSF1A promotes acute kidney injury by activating NF-κB pathway.","authors":"Minjie Zhang, Yankun Li, Chunyu Wu, Quanren Pan, Peng Wang, Hua-Feng Liu","doi":"10.1186/s11658-026-00913-z","DOIUrl":"10.1186/s11658-026-00913-z","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) is closely linked to inflammatory responses driven by the NF-κB pathway, yet the epigenetic mechanisms underlying this association remain poorly understood. This study investigates the role of N-acetyltransferase 10 (NAT10)-mediated RNA N⁴-acetylcytidine (ac⁴C) modification in regulating NF-κB signaling during AKI.</p><p><strong>Methods: </strong>Clinical AKI specimens and experimental models (in vivo and in vitro) were analyzed to assess NAT10 expression in renal tubular epithelial cells (RTECs). Genetic knockdown and overexpression of NAT10 (including the catalytically inactive NAT10-G641E mutant) were performed in vitro to evaluate NF-κB pathway activity and hypoxia/reoxygenation (H/R)-induced inflammatory responses. In murine ischemia/reperfusion (I/R)-induced AKI models, genetic ablation of NAT10 in RTECs and pharmacological inhibition using Remodelin were employed to study renal inflammation and injury. Mechanistic insights were derived from integrated ac⁴C acetylated RNA immunoprecipitation sequencing (acRIP-seq) and RNA sequencing (RNA-seq) analyses to identify NAT10-mediated ac⁴C modification targets and their effects on RNA stability, translation efficiency, and signaling pathways.</p><p><strong>Results: </strong>NAT10 was significantly upregulated in RTECs of clinical AKI specimens and experimental models. In vitro, NAT10 knockdown suppressed NF-κB activation, mitigating H/R-induced inflammation and cellular damage, while NAT10 overexpression (but not the G641E mutant) activated NF-κB, exacerbating RTECs injury. In murine I/R-AKI models, genetic or pharmacological inhibition of NAT10 attenuated NF-κB-mediated renal inflammation and tubular damage. Mechanistically, NAT10-mediated ac⁴C modification enhanced RNA stability and translation efficiency of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), leading to aberrant NF-κB activation and subsequent inflammatory cascades.</p><p><strong>Conclusions: </strong>This study identifies the NAT10-ac⁴C-TNFRSF1A axis as a novel epigenetic regulator of NF-κB-driven renal inflammation in AKI. NAT10 promotes inflammatory signaling and tubular damage by enhancing TNFRSF1A mRNA stability and translation efficiency, highlighting its potential as a therapeutic target. These findings provide a theoretical foundation for developing AKI treatments targeting NAT10-mediated ac⁴C modification to mitigate NF-κB-dependent pathology.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927027","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":"Rv1983 promotes mycobacterial dissemination by triggering ferroptosis through GPX4 ubiquitination.","authors":"Zilu Qu, Yuanyuan Zhou, Qinzhen Cai, Tian Chen, Yun Xiang, Liuqing Chen, Chunhui Yuan","doi":"10.1186/s11658-026-00942-8","DOIUrl":"10.1186/s11658-026-00942-8","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, a unique form of regulated cell death induced by iron-dependent lipid peroxidation, has been implicated in the pathogenesis of Mycobacterium tuberculosis (Mtb). However, the role of Mtb proteins, particularly those encoded by the genomic regions of deletion (RDs), involved in mediating macrophage ferroptosis has not been thoroughly investigated. This study aimed to screen for Mtb RD region-encoded proteins that induce macrophage ferroptosis and elucidate the underlying molecular mechanisms.</p><p><strong>Methods: </strong>We identified the Rv1983 protein with cytotoxic activity against murine bone marrow-derived macrophages (BMDMs) through screening of prokaryotically expressed Mtb RDs proteins, and subsequently determined the specific cell death modality induced by Rv1983 in BMDMs through flow cytometry, western blotting, and cytotoxicity assays following Rv1983 stimulation. To investigate the role of Rv1983 in Mtb infection, we constructed an Rv1983-knockout Mtb H37Ra strain (H37RaΔRv1983) and compared its intracellular and extracellular bacterial loads with wild-type H37Ra strain in infected BMDMs. Using coimmunoprecipitation, immunofluorescence, and flow cytometry, we identified and validated the target protein of Rv1983 in macrophages and its functional role in Rv1983-mediated macrophage death. For in vivo validation, wild-type H37Ra and H37RaΔRv1983 strains were used to infect both wild-type and macrophage-specific Rv1983-binding protein knockout mice, and the role of Rv1983 during Mtb infection was assessed through bacterial colony counting, flow cytometry analysis, and histochemical staining.</p><p><strong>Results: </strong>This study identifies Rv1983 (PE_PGRS35), an RD2-encoded secreted protein of Mtb that acts as a ferroptosis effector to promote mycobacterial dissemination. Mechanistically, Rv1983 binds to E3 ubiquitin ligase tripartite motif 25 (TRIM25) in macrophages through its PE domain, especially on the Y62 site. The Rv1983-TRIM25 complex interacts with glutathione peroxidase 4 (GPX4), and subsequently promotes K48-linked ubiquitination degradation of GPX4 at the K75 site, ultimately inducing ferroptosis to promote mycobacterial dissemination. An Rv1983-deficient Mtb strain (H37RaΔRv1983) displayed significant suppression of Mtb dissemination both in vitro and in vivo.</p><p><strong>Conclusions: </strong>These findings provide a new insight into the molecular mechanism of Mtb-induced ferroptosis, and suggest that targeting ferroptosis mediated by the Rv1983-TRIM25-GPX4 signaling axis is a potential strategy for therapeutic control of tuberculosis.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873535","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":"RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.","authors":"Ji-Fang Zhang, Long-Tian Li, Yue-Ying Yang, Shi-Chen Zhang, Chao Gao, Xu Zhu, He Xin, Xin-Yang Li","doi":"10.1186/s11658-026-00940-w","DOIUrl":"10.1186/s11658-026-00940-w","url":null,"abstract":"<p><p>Melanoma is an aggressive type of cancer that is prone to developing resistance to targeted therapies and immunotherapies, so it is necessary to seek novel therapeutic opportunities. RING finger E3 ubiquitin ligases (RNFs) play a crucial role in the ubiquitin-proteasome system and are important in regulating the development of melanoma by orchestrating various pathways. In this review, we analyze the structural and functional characteristics of the RNF subfamily to clarify their mechanisms of action in melanoma and to compare the functional differences among various RNFs. Additionally, we systematically evaluate potential therapeutic strategies targeting RNFs, including small-molecule drugs, proteolysis-targeting chimeras (PROTACs), and molecular glues, and further propose new directions for drug design by using computer-aided technology. Furthermore, this review suggests that RNF-targeted therapy should be combined with existing therapies, providing a novel approach for the precise treatment of melanoma, and is significant for clinical application and drug development.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855915","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}