Cellular & Molecular Biology Letters最新文献

{"title":"Correction: LncRNA H19 promotes the differentiation of bovine skeletal muscle satellite cells by suppressing Sirt1/FoxO1.","authors":"Xiaochun Xu, Shengyue Ji, Weili Li, Bao Yi, Hengxin Li, Hongfu Zhang, Wenping Ma","doi":"10.1186/s11658-026-01021-8","DOIUrl":"https://doi.org/10.1186/s11658-026-01021-8","url":null,"abstract":"","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting biglycan-TLR2/TLR4 interaction with synthetic peptides mitigates inflammation and ameliorates renal function in ischemia-reperfusion injury.","authors":"Rosetta Merline, Louise Tzung-Harn Hsieh, Jinyang Zeng-Brouwers, Rajkumar Vutukuri, David C Briggs, Anthony J Day, Malgorzata Wygrecka, Szymon Nowak, Rafal Bartoszewski, Liliana Schaefer","doi":"10.1186/s11658-026-01019-2","DOIUrl":"10.1186/s11658-026-01019-2","url":null,"abstract":"<p><strong>Background: </strong>Renal ischemia-reperfusion injury (IRI), characterized by enhanced inflammation, is a leading cause of acute kidney injury (AKI) with limited treatments beyond supportive dialysis. Biglycan through toll-like receptors (TLR)2/TLR4 signaling aggravates tissue damage in acute renal IRI. This study aimed to identify the TLR2/TLR4 binding sites of biglycan and test the efficacy of biglycan-derived peptides in vitro and in vivo.</p><p><strong>Methods: </strong>Epitope mapping was conducted using PepSpot peptide arrays with overlapping 15-mer biglycan peptides. Binding of wildtype (WT) and mutant biglycan proteins and synthesized peptides to TLR2 and TLR4 was analyzed by microscale thermophoresis. Nuclear Factor (NF)-κB activation was assessed in HEK-Blue-TLR2 and HEK-Blue-TLR4 reporter cells following stimulation with biglycan variants and peptides. Primary murine and human monocyte-derived macrophages were used to evaluate inflammatory responses in vitro. Renal IRI was induced in C57BL/6 mice with intravenous peptide treatment administered prior to surgery. Renal function, immune cell infiltration, and cytokine expression were assessed using serum creatinine measurements, immunohistochemistry, and molecular analyses.</p><p><strong>Results: </strong>PepSpot epitope mapping identified ₁₁₃LQHLYA₁₁₈ and ₃₀₂LQVVYL₃₀₇ as the TLR2/TLR4 binding sequences in leucine-rich repeat (LRR) 2 and LRR10, respectively. Sequence-swapped (swLRR2 and swLRR10) and point mutant (LRR2ΔF and LRR10ΔF) biglycans exhibited decreased binding to TLR2 and TLR4 than WT-biglycan. Compared with WT-biglycan, these mutants elicited reduced NF-κB activation in HEK-Blue-TLR2 and HEK-Blue-TLR4 cells, consistent with decreased TNFα, CCL2, and CXCL1 expression in primary murine macrophages. Peptides 1 and 2, containing the ₁₁₃LQHLYA₁₁₈ and ₃₀₂LQVVYL₃₀₇ sequences of LRR2 and LRR10, respectively, exhibited significant binding affinity to TLR2 and TLR4 and inhibited biglycan-induced NF-κB activation, ERK phosphorylation, and TNFα, CCL2, and CXCL1 expression. These findings were corroborated in human monocyte-derived macrophages. In the renal IRI mouse model, peptide treatment mitigated immune cell infiltration, decreased Cxcl1 ,Ccl2, and Tnfα expression, and improved renal function, evidenced by lower serum creatinine.</p><p><strong>Conclusions: </strong>The findings delineate conserved biglycan-TLR2/TLR4 recognition sequences and design of inhibitory peptides with therapeutic efficacy in vitro and in vivo. Peptides that inhibit biglycan-TLR2/TLR4 binding offer a targeted therapeutic approach for mitigating biglycan-TLR-associated sterile and pathogen-induced inflammatory diseases, with significant translational relevance for IRI.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073535","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":"Emerging roles of α/β hydrolase domain (ABHD) proteins in S-palmitoylation modification: molecular mechanisms, structural features, and pathological implications.","authors":"Xin Wen, Mingyang Liu, Yabing Quan, Yichen Xu, Jun Xu, Xuemeng Shi","doi":"10.1186/s11658-026-01020-9","DOIUrl":"https://doi.org/10.1186/s11658-026-01020-9","url":null,"abstract":"<p><p>S-palmitoylation, a reversible post-translational modification, regulates critical biological processes and represents a promising therapeutic target for diverse human diseases. Over the past decade, human α/β hydrolase domain (ABHD) proteins have emerged as key regulators of the dynamic S-palmitoylation/depalmitoylation cycle, yet a systematic overview of their roles in this modification remains lacking. This review provides a comprehensive summary of the functions of emerging ABHD proteins-including ABHD17A/B/C, ABHD16A, ABHD10, ABHD7, and ABHD8-in the dynamics of S-palmitoylation and depalmitoylation cycle, along with their molecular mechanisms, structural features, and substrate specificities. Associations between dysregulated ABHD protein-mediated S-palmitoylation and various diseases, including cancers, neurological disorders, degenerative diseases, viral infectious diseases, metabolic diseases, and reproductive disorders are discussed. Predictive criteria for uncharacterized ABHD proteins and prospective targeted therapeutic strategies are also proposed. This review provides mechanistic insights into emerging ABHD proteins in S-palmitoylation/depalmitoylation, and lays a foundation for developing novel diagnostic markers and precision therapies for S-palmitoylation-related diseases.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104649","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":"ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.","authors":"Fushuang Zheng, Rongli Guan, Xiaojin Yu, Jiaxin Yang, Hai Zhao, Fan Yang","doi":"10.1186/s11658-026-00995-9","DOIUrl":"10.1186/s11658-026-00995-9","url":null,"abstract":"<p><p>The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705434","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":"The origin and function of the posterior ring in mouse sperm head.","authors":"Bingbing Wu, Chenghong Long, Jiayi Liu, Zuobin Zhu, Liling Liu, Qingling Ma, Yan Long, Liying Wang, Huafang Wei, Yanjie Ma, Jingwen Hou, Heying Li, Li Yuan, Wei Li, Chao Liu","doi":"10.1186/s11658-026-00997-7","DOIUrl":"https://doi.org/10.1186/s11658-026-00997-7","url":null,"abstract":"<p><strong>Background: </strong>Despite extensive characterization of sperm structures, certain specialized subcellular structures are still not well understood. Among these, the posterior ring has been recognized for over half a century; yet, its molecular composition and biological role remain unknown. This research aims to define the molecular components and functional roles of the sperm posterior ring.</p><p><strong>Methods: </strong>3D-rendered confocal microscopy was used to determine the localization and developmental dynamics of SPEM3 and TEX50 in mature spermatozoa and spermatids at different steps of spermiogenesis. Spem3 and Tex50 knockout mouse models were generated to explore their physiological functions. Sperm morphology and ultrastructure were investigated through immunofluorescence along with transmission and scanning electron microscopy, whereas sperm motility was evaluated using computer-assisted sperm analysis. Proteomics, coimmunoprecipitation, and immunoblotting were performed to identify SPEM3 and TEX50 as structurally interdependent interacting components of the posterior ring and to elucidate how their loss disrupts sperm architecture and fertility.</p><p><strong>Results: </strong>We identified SPEM3 as a core component of the posterior ring located at the sperm head-tail linkage. The posterior ring arises from the marginal ring at the acroplaxome periphery during early spermiogenesis. Loss of Spem3 led to severe bending of the head-tail linkage, accompanied by a marked reduction in sperm motility, ultimately leading to male infertility. Furthermore, SPEM3 interacts and colocalizes with TEX50, and deficiency of either protein resulted in similar phenotypes, including disorganization of the posterior ring and postacrosomal region as well as impairment of the sperm connecting piece.</p><p><strong>Conclusions: </strong>These findings establish SPEM3 and TEX50 as critical posterior ring components essential for maintaining postacrosomal integrity and anchoring the sperm head to the tail. By resolving the long unknown molecular composition of the posterior ring, this study provides new mechanistic insight into sperm head-tail integrity and the pathogenesis of certain forms of male infertility.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grx2 deficiency accelerates BMSC senescence and senile osteoporosis via CD36 S-glutathionylation.","authors":"Muzhe Li, Taxi Wumiti, Jie Sun, Tianchi Zhang, Lining Wang, Qinfeng Zhou, Tianwei Xia, Jirong Shen, Yafeng Zhang, Yong Ma, Yang Guo","doi":"10.1186/s11658-026-00999-5","DOIUrl":"10.1186/s11658-026-00999-5","url":null,"abstract":"<p><strong>Rationale: </strong>Senile osteoporosis (SOP) is driven largely by bone marrow mesenchymal stem cell (BMSC) senescence and mitochondrial dysfunction. S-glutathionylation is an important redox modification regulating mitochondrial homeostasis, yet its role in skeletal aging remains unclear. The objective of this study is to systematically investigate the role of Grx2 deficiency-mediated CD36 S-glutathionylation in BMSC senescence and SOP development.</p><p><strong>Methods: </strong>Grx2, p53, and p21 expression in human and mouse BMSCs were analyzed by immunohistochemistry (IHC), western blotting (WB), and polymerase chain reaction (PCR). Aging-related and ovariectomy-induced osteoporosis models were established in Grx2^-/^- mice for bone metabolism and senescence assessments. BMSC senescence, osteogenesis, and adipogenesis were evaluated by SA-β-Gal and WB, ALP/ARS staining, and ORO staining. Transcriptomic and S-glutathionylated proteomic analyses were performed to identify underlying mechanisms. Fatty acid uptake was quantified using two-color flow cytometry. DAG and MDA levels were measured to assess lipid overload and oxidative injury. Mitochondrial structure and function were evaluated by TEM, Mitotracker, qPCR, NAD⁺/NADH, ATP, ROS, JC-1, and Seahorse assays. The PI3K/AKT pathway was assessed by WB. Co-IP confirmed CD36 S-glutathionylation, and molecular docking predicted C272 as the key modification site. CD36-C272S mutation and Grx2 overexpression were applied to validate functional mechanisms in vitro and in vivo.</p><p><strong>Results: </strong>Grx2 deficiency, in both male and ovariectomized female mice, accelerates bone loss, inhibits osteoblast formation without altering osteoclast function, and exacerbates BMSC senescence. Through integrated transcriptomic and S-glutathionylated proteomic analysis, we identified the fatty acid transporter CD36 as a critical downstream target of Grx2. Notably, Grx2 deficiency markedly increases the S-glutathionylation of CD36, which not only enhances its fatty acid uptake capacity, leading to the accumulation of toxic lipid metabolites and oxidative damage, but also impairs mitochondrial energy metabolism by inhibiting the PI3K/AKT signaling pathway. Overexpression of Grx2 or the C272S mutation in CD36, which disrupts its S-glutathionylation, can break this harmful cycle and inhibit BMSC senescence.</p><p><strong>Conclusions: </strong>Grx2 deficiency-mediated CD36 S-glutathionylation drives BMSC senescence and SOP, providing new insight into the redox regulatory mechanisms underlying skeletal aging.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547952","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":"TLR4-dependent upregulation of IL-22-producing T cells in the bone niche links to the imbalance of bone homeostasis.","authors":"Ji-Eun Kim, Jinyoung Go, Eun-Jin Lee, Sang-Min Kim, Dawon Jung, Huiwon No, Minsuk Hyun, Yeo-Jin Lee, Yoolim Sung, Min Kyeong Ju, Yoojeong Hwang, Eunwoo Lee, Seong Who Kim, Eun-Ju Chang","doi":"10.1186/s11658-026-00994-w","DOIUrl":"10.1186/s11658-026-00994-w","url":null,"abstract":"<p><strong>Background: </strong>Toll-like receptor 4 (TLR4) activation within the bone marrow (BM) microenvironment regulates proinflammatory cytokines and chemokines, which influence immune activity and bone remodeling. However, the immune cell factors mediating TLR4-dependent cross-talk in the bone/BM microenvironment remain insufficiently defined.</p><p><strong>Methods: </strong>We provide a transcriptomic analysis of significant cellular and immune changes in total BM cells of wild-type mice following lipopolysaccharide (LPS)-induced TLR4 activation in vivo compared with TLR4 knockout (KO) mice. To obtain direct evidence that interleukin (IL)-22 contributes to TLR4-driven bone destruction, we analyzed their bone phenotypes following LPS injection into IL-22 KO mice. In addition, co-culture of pre-osteoblasts (OBs) and BM cells was conducted to evaluate the effect of IL-22 in osteoclast (OC) formation in a pre-OB-dependent manner.</p><p><strong>Results: </strong>Differentially expressed gene analysis from BM cells of wild-type (WT) mice revealed an increase in IL-22-producing cells, along with increased IL-22 production in a TLR4-dependent manner. Flow cytometry confirmed that LPS enhanced the number of CD4⁺IL-22⁺ cells in the BM and decreased in TLR4-deficient BM. LPS also enhanced the differentiation of CD4⁺IL-22⁺ T cells and promoted IL-22 induction in T cells. IL-22 KO mice showed minimal LPS-induced bone loss, whereas WT mice exhibited severe bone destruction with increased formation of tartrate-resistant acid phosphatase-positive OCs. Interestingly, while IL-22 did not directly affect OC differentiation, IL-22 enhanced OC differentiation only when BM cells were co-cultured with pre-OBs through the elevation of the receptor activator of nuclear factor-κB ligand (RANKL) in pre-OBs during osteogenesis. Mechanistically, IL-22 induced cyclooxygenase-2 in pre-OBs through extracellular signal-regulated kinase and p38 signaling, driving prostaglandin E2 production and subsequent RANKL induction.</p><p><strong>Conclusions: </strong>TLR4 activation enhanced IL-22 production in T cells, which stimulates RANKL production in pre-OBs to further induce OC formation. These results support that IL-22 acts as a TLR4-driven mediator to shift bone remodeling toward catabolic bone degeneration.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454724","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":"Single-cell and spatial transcriptomic analysis reveal distinct tumor microenvironment signatures in primary and recurrent hypopharyngeal squamous cell carcinoma.","authors":"Zhimou Cai, Jinhong Zhang, Yaodong Ding, Zhenglin Xu, Zhi Liu, Zhiwei Qiang, Zhaoyue Lu, Lin Chen, Weiping Wen, Wenbin Lei","doi":"10.1186/s11658-026-00991-z","DOIUrl":"10.1186/s11658-026-00991-z","url":null,"abstract":"<p><strong>Background: </strong>Hypopharyngeal squamous cell carcinoma (HPSCC) is a rare, highly aggressive malignancy, with recurrence playing a pivotal role in treatment failure and cancer-related mortality. The tumor microenvironment (TME) characteristics and molecular mechanisms driving recurrence in HPSCC remain poorly defined.</p><p><strong>Materials and methods: </strong>Primary HPSCC (P-HPSCC) samples (n = 6) and recurrent HPSCC (R-HPSCC) samples (n = 3) were analyzed. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were employed to dissect the cellular composition and molecular characteristics of the TME. Key regulatory networks were identified through gene expression analysis, pathway enrichment, and intercellular communication profiling. Functional validation experiments were performed to confirm the biological relevance of the pathways identified.</p><p><strong>Results: </strong>ScRNA-seq analysis revealed that malignant epithelial cells (maEpCs) in recurrent tumors exhibited increased stemness, epithelial-mesenchymal transition (EMT), and immune evasion programs. Mechanistically, IGF2BP2 was selectively upregulated in R-HPSCC and functioned as an m⁶A reader to stabilize SMAD3 mRNA, thereby activating transforming growth factor beta (TGF-β) signaling and facilitating malignant progression. Integrated spatial transcriptomics and functional assays demonstrated that cancer-associated fibroblasts in recurrent tumors promote progression via FN1-mediated signaling. Concurrently, the recurrent TME underwent myeloid remodeling toward an immunosuppressive state, characterized by increased infiltration of SPP1⁺ tumor-associated macrophages and further enrichment of LAMP3⁺ dendritic cells with impaired antigen-presenting capacity, alongside aggravated CD8⁺ T-cell exhaustion, marked by upregulation of CTLA4 as a potential immune escape driver.</p><p><strong>Conclusions: </strong>This study identifies recurrence-associated cellular and molecular features in HPSCC. Recurrent tumors exhibited maEpC reprogramming via IGF2BP2-mediated activation of TGF-β signaling, coupled with FN1-dependent stromal activation and immune evasion marked by myeloid immunosuppressive remodeling and CD8⁺ T-cell exhaustion, characterized by CTLA4 upregulation. Collectively, these findings reveal a pro-recurrent TME and suggest potential therapeutic targets in R-HPSCC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435255","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":"Microbiota-mediated modulation of the tumor microenvironment in urological cancers: crosstalk between gut and intratumoral microbiota.","authors":"Zhibiao Li, Haoxiang Xu, Lin Yang, Jun Zheng, Weijia Li, Rulin Liao, Wenxue Huang, Boyuan Sun, Zhuohang Li, Cunzhen Ma, Xunguo Yang, Peidan Peng, Jie Zhao, Bisheng Cheng, Peng Wu","doi":"10.1186/s11658-026-00951-7","DOIUrl":"https://doi.org/10.1186/s11658-026-00951-7","url":null,"abstract":"<p><p>Recent studies indicate the gut microbiome as a crucial regulator of cancer therapy, yet its role in urological malignancies remains incompletely understood. High rates of resistance to cornerstone treatments, including immune checkpoint inhibitors (ICIs) and intravesical immunotherapy, represent major clinical hurdles. Synthesizing emerging evidence on the gut-tumor axis shows how the gut, urobiome, and intratumoral microbiota (IM) collectively influence the tumor microenvironment (TME) and therapeutic outcomes. This influence extends beyond chronic inflammation and direct genotoxicity to include metabolic crosstalk that shapes the host immune landscape. The composition of the gut microbiota is emerging as a potential predictive marker for ICI efficacy, as the enrichment of certain beneficial taxa has been linked to favorable outcomes. Microbial metabolic pathways are also implicated in therapeutic resistance; microbial metabolism of host hormonal precursors is hypothesized as one mechanism contributing to resistance to endocrine therapies. Furthermore, systemic and local communities may interact, wherein gut-derived metabolites can enhance systemic immunotherapy, while the local urobiome may interfere with intravesical treatment efficacy. However, clinical translation faces major impediments. A primary challenge is the lack of methodological standardization, which generates observational inconsistencies and complicates causal inference. Future progress will therefore depend on large-scale, longitudinal, multiomics clinical trials using harmonized protocols. This review provides a comparative narrative synthesis of shared and distinct mechanisms across the three major urological cancers and outlines priorities for future interventions and precision medicine in urologic oncology.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise suppresses IP6K3 to modulate BCAA metabolism and ferroptosis in MASLD.","authors":"Zi-Chen Li, Fang-Fang Xu, Yi Zhao, Chen-Rui Shen, Xin-Yi Song, Yu-Ping Xu, Hui Guo, Jiang-Tao Fu, Xuan-Yi Tao, Jun Ren, Ling Lin, Dong-Jie Li, Hui Fu, Fu-Ming Shen","doi":"10.1186/s11658-026-00981-1","DOIUrl":"10.1186/s11658-026-00981-1","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to branched-chain amino acid (BCAA) dysmetabolism and ferroptosis, and exercise is considered protective, yet the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Integrated bioinformatic analyses of public datasets were performed to identify key regulators of MASLD. Hepatic inositol hexakisphosphate kinase 3 (IP6K3) expression was examined in liver samples from patients with MASLD as well as mice. The functional role of IP6K3 was assessed by either hepatocyte-specific Ip6k3 deletion or exercise intervention in mice. Single-cell RNA sequencing (scRNA-seq), IP6K3 overexpression and knockdown, liquid chromatography-tandem mass spectrometry, and co-immunoprecipitation were used to explore the underlying mechanism by which IP6K3 regulates MASLD.</p><p><strong>Results: </strong>Hepatic IP6K3 was significantly upregulated in both patients with MASLD as well as mice, and exercise markedly attenuated hepatic IP6K3 expression in MASLD mice. Hepatocyte-specific Ip6k3 deletion conferred resistance to MASLD-induced liver injury. scRNA-seq revealed that these protective effects were related to enhanced BCAA degradation and inhibition of ferroptosis. Further studies showed that BCAA degradation was dependent on branched-chain aminotransferase 2 (BCAT2). In vitro, IP6K3 overexpression exacerbated BCAA-promoted ferroptosis, which was rescued by ferrostatin-1. Conversely, IP6K3 knockdown prevented ferroptosis, and this effect was abolished by inhibiting BCAT2. Mechanistically, elevated IP6K3 in MASLD could bind to heterogeneous nuclear ribonucleoprotein K (HNRNPK) in hepatocytes. Exercise-downregulated IP6K3 facilitated HNRNPK release, thereby stabilizing BCAT2 mRNA, promoting BCAA catabolism, and ultimately preventing ferroptosis in MASLD.</p><p><strong>Conclusions: </strong>Our study identifies IP6K3 as a key molecule in exercise-induced protection against MASLD, and suggests that IP6K3 inhibition might represent a potential pharmacological strategy for MASLD intervention.</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/PMC13628866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410494","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}