Molecular biomedicine最新文献

{"title":"Aryl hydrocarbon receptor is involved in DNA damage repair after liver injury with diethylnitrosamine in mice.","authors":"Beatriz Marín-Díaz, Francisco Javier González-Rico, Laura Ordóñez-Mata, Ángel C Román, Jaime M Merino, Pedro M Fernández-Salguero","doi":"10.1186/s43556-026-00596-0","DOIUrl":"10.1186/s43556-026-00596-0","url":null,"abstract":"<p><p>Aryl hydrocarbon receptor (AhR) is a transcription factor traditionally involved in toxicological and carcinogenic cellular processes linked to xenobiotics. In recent decades, a new physiological role has emerged, in which AhR has been shown to be a key regulator of different processes such as the cell cycle, cell proliferation, apoptosis, pluripotency, and stemness. Recent studies have suggested a possible role for AhR in the DNA damage response (DDR) and repair mechanisms. To assess this point, in this work we used diethylnitrosamine (DEN) to induce liver injury and DNA damage in wild type (WT) and AhR knockout (KO) mice. We analysed the protein expression levels of several DDR (H2AX, 53BP1, and BRCA1) and cell proliferation (Ki67, AFP, and PCNA) markers. Therefore, we demonstrate that following DNA damage, the absence of AhR results in a shift towards apoptosis and compensatory proliferation mechanisms, accompanied by reduced repair fidelity of DNA damage compared with than in WT mice, compromising genomic stability. We also mapped the interactome profile of AhR, identifying new partners involved in both repair and proliferation processes. In conclusion, our results highlight the relevant role of AhR in cell proliferation and DNA repair processes, which can be key in different pathologies, such as cancer.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MFSD2A in health and disease: lysolipid transport, barrier physiology, and translational boundaries.","authors":"Jinheng Gan, Yang Chen, Lin Xin","doi":"10.1186/s43556-026-00585-3","DOIUrl":"10.1186/s43556-026-00585-3","url":null,"abstract":"<p><p>Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a sodium-dependent lysolipid transporter that delivers lysophosphatidylcholine-bound fatty acids, particularly docosahexaenoic acid, across specialized cellular interfaces. This Review synthesizes structural, biochemical, physiological, genetic, and disease evidence through an evidence-weighted transport-to-barrier-to-disease framework. We first examine substrate recognition, sodium coupling, conformational transport, and the membrane lipid consequences of lysophosphatidylcholine uptake. We then detail the best-established physiological setting, central nervous system endothelium, where MFSD2A supports brain docosahexaenoic acid accretion, blood-brain barrier maturation, and suppression of caveolae-mediated transcytosis. Evidence from the retina, placenta, lung, kidney, epidermis, and immune cells is compared to define tissue-specific deployment rather than a universal downstream pathway. Rare biallelic variants and experimental loss-of-function models provide the strongest disease evidence, linking impaired lysolipid transport to deficient brain lipid supply, microcephaly, and neurodevelopmental abnormalities. Acquired vascular injury studies associate MFSD2A dysregulation with barrier leakage, whereas proposed roles in cancer, immunotherapy response, and patient stratification remain context-dependent and largely associative. We also assess translational concepts, including barrier stabilization, central nervous system drug delivery, biomarker development, and structure-guided modulation, emphasizing unresolved requirements for selectivity, reversibility, safety, and prospective validation. By distinguishing transporter-intrinsic mechanisms from secondary lipid remodeling and disease correlations, this Review clarifies which functions are established, which are tissue restricted, and which remain hypotheses. This framework identifies experimental priorities for linking MFSD2A activity to clinically informative phenotypes without extrapolating beyond current evidence.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mRNA lipid nanoparticle vaccines: current status, challenges and future prospects.","authors":"Zhineng Wu, Jinghu Lou, Yi Cheng, Meng Li, Zengming Wang, Nan Liu, Xiang Gao, Aiping Zheng, Hui Zhang","doi":"10.1186/s43556-026-00600-7","DOIUrl":"10.1186/s43556-026-00600-7","url":null,"abstract":"<p><p>mRNA vaccines have become a clinically validated vaccine platform, as demonstrated by the success of COVID-19 vaccines such as Comirnaty and Spikevax, owing to their rapid design, manufacturing scalability, and capacity to induce in situ antigen expression. A key factor underlying this success is the lipid nanoparticle (LNP) delivery system, which protects mRNA from degradation and promotes efficient cellular uptake and cytoplasmic delivery, thereby enabling the full potential of mRNA technology. The continued advancement of mRNA-LNP vaccines requires integrated optimization of mRNA design, LNP composition, and delivery strategies to achieve improved stability, efficient intracellular delivery, and balanced immune responses. Despite remarkable progress, challenges related to formulation stability, long-term storage stability, safety and reactogenicity concerns, and durability of immune protection continue to hinder the broader application of mRNA-LNP vaccine platforms. This review provides an integrated overview of recent advances in mRNA-LNP vaccines, covering mRNA molecular engineering, LNP composition and delivery mechanisms, immune responses, clinical progress, and current developmental challenges. Furthermore, emerging strategies, including thermostable formulations, next-generation LNPs with improved targeting capability, emerging RNA platforms, and artificial intelligence-assisted optimization of RNA sequences and lipid materials, are discussed. By summarizing current achievements and future opportunities, this review highlights key principles guiding the rational design of safer, more stable, and more precise mRNA-LNP vaccine platforms and provides insights into accelerating their clinical translation.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Troponin: biology, molecular mechanisms, and multidimensional clinical applications.","authors":"Michaela Adamcova, Lukáš Petráň","doi":"10.1186/s43556-026-00597-z","DOIUrl":"10.1186/s43556-026-00597-z","url":null,"abstract":"<p><p>Troponin is classically recognized as the central regulator of striated muscle contraction. However, emerging evidence indicates that troponin subunits are also expressed in numerous non-muscle cell types, where they perform diverse non-classical functions independent of contractile regulation. Recent studies have implicated troponin in transcriptional regulation, epigenetic remodeling, mitochondrial bioenergetics, and calcium signaling. Troponin has also been shown to inhibit angiogenesis and is present in extracellular vesicles. Together, these findings suggest that troponin participates in fundamental cellular processes that extend far beyond muscle physiology. Despite these advances, the molecular mechanisms underlying these non-classical functions remain incompletely understood, and the relationship between troponin's structural biology and its roles in both cancerous and non-cancerous cells has been only partially explored. In this review, we integrate current experimental evidence with recent bioinformatic analyses to provide a comprehensive overview of troponin biology beyond the sarcomere. Particular emphasis is placed on the molecular mechanisms governing nuclear localization, protein-protein interactions, transcriptional and epigenetic regulation, and mitochondrial function, as well as on the distinct biological roles of individual troponin isoforms. We further discuss the growing evidence linking aberrant troponin expression and function to cancer biology, highlighting its context- and isoform-dependent activities that may either promote or suppress tumor development. Collectively, these findings redefine troponin as a multifunctional regulatory protein and identify it as a promising subject for future research.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.","authors":"Yue Pan, Wan-Hong Li, Wei Zhang, Wan-Jing Ma, Hui Sun","doi":"10.1186/s43556-026-00599-x","DOIUrl":"10.1186/s43556-026-00599-x","url":null,"abstract":"<p><p>Cardiovascular disease progression is shaped by a close interaction between metabolic adaptation and inflammatory signaling. In injured cardiac and vascular tissues, ischemia, pressure overload, lipid stress and metabolic excess reshape how cardiomyocytes, endothelial cells, immune cells and fibroblasts sense damage and communicate with their microenvironment. Cardiovascular inflammation follows a staged tissue response, from danger-signal sensing and nuclear factor-κB-related priming to inflammasome activation, cytokine amplification, leukocyte recruitment, efferocytosis and chronic remodeling. Metabolic reprogramming shapes this sequence by altering substrate use, redox control, biosynthetic routing and metabolite signaling. A major challenge is that glycolysis, fatty acid oxidation and amino-acid metabolism do not carry fixed biological meanings; their effects depend on the cell type, measurement layer and disease phase in which they occur. This review examines metabolism-inflammation crosstalk in cardiovascular disease by linking core inflammatory pathways with metabolic sensors, immune-cell metabolic reprogramming and signaling metabolites, then comparing disease-specific mechanisms in myocardial infarction/ischemia-reperfusion injury, heart failure, atherosclerosis, hypertrophic remodeling and myocardial fibrosis. We emphasize how apparently similar metabolic shifts can represent adaptive repair, inflammatory amplification or maladaptive remodeling in different compartments. The therapeutic discussion separates pathway activity from targetability and uses anti-inflammatory trials and metabolic interventions to define when patient selection, pathway engagement and safety considerations support targeted treatment.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Craniofacial development: genetics, signaling pathways, teratogenic mechanisms, and clinal significance.","authors":"Xinli Lv, Juan Du","doi":"10.1186/s43556-026-00574-6","DOIUrl":"10.1186/s43556-026-00574-6","url":null,"abstract":"<p><p>Craniofacial development is a highly coordinated and stage-specific process involving neural crest cell migration, proliferation, differentiation, and epithelial-mesenchymal transition. Genetic mutations, signaling pathway abnormalities, and exposure to environmental teratogens can disrupt normal development. These anomalies can lead to cleft palate, craniosynostosis, and other common congenital craniofacial malformations. Although significant progress has been made in understanding craniofacial development in recent years, the systematic integration of these factors remains limited. Here, we provide a comprehensive review of the cellular and molecular mechanisms underlying normal craniofacial development, focusing on the coordinated regulation of cranial neural crest cells by transcription factors, signaling pathways and epigenetic programs. We further summarize major pathogenic mechanisms implicated in craniofacial disorders. Additionally, the teratogenic mechanisms underlying maternal endogenous and external environmental exposures are explored, with particular emphasis on their interactions with genetic factors in reshaping developmental trajectories. We emphasize the central role of gene-environmental interactions in craniofacial pathogenesis by integrating evidence from developmental biology, multi-omics studies and clinical studies. Subsequently, we outline current clinical diagnostic techniques and management strategies for craniofacial malformations, pointing out the existing challenges and future directions. This review establishes a comprehensive framework linking gene regulation, metabolic environment, and clinical implications. It is expected to facilitate deeper insights into disease mechanisms and promoting the translation of basic research findings into clinical diagnosis, prevention, and management of craniofacial disorders.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DCBLD2 super-enhancer drives colorectal cancer progression through FOSL2/JUND-mediated activation of the CD146/AKT/TNFRSF6B pathway.","authors":"Tong Wu, Lan Shao, Xin Hu, Hongjuan He, Lu Chen, Meiqi Feng, Chengjin Qi, Ziwen Wang, Haoran Yu, Boshu Ji, Yijia Cao, Yan Zhang, Qiong Wu","doi":"10.1186/s43556-026-00592-4","DOIUrl":"10.1186/s43556-026-00592-4","url":null,"abstract":"<p><p>Super-enhancers are clusters of cis-regulatory elements that sustain the expression of cell-identity genes. Their aberrant activation or dysfunction constitutes a hallmark of malignant cellular transformation, which frequently rewires oncogenic transcriptional programs to support uncontrolled cell proliferation and metastatic potential. However, the functions and epigenetic regulation mechanisms of colorectal cancer specific super-enhancers remain poorly understood, and few studies have focused on dissecting how tumor enriched super-enhancers mediate downstream oncogenic signaling in CRC. By integrating multi-omics sequencing data, we identified a highly active super-enhancer in colorectal cancer, termed DCBLD2-SE. Through luciferase reporter assays, the SE3-2 subregion was identified as the minimal functional core of this super-enhancer. Mechanistic studies confirmed that transcription factors of the activator protein-1 family (FOSL2 and JUND) can bind directly to the SE3-2 cis-regulatory element, synergistically regulating local chromatin remodeling and strongly driving the upregulation of the target gene DCBLD2. Following knockout of the DCBLD2-SE core region, the malignant proliferative capacity of colorectal cancer cells decreased significantly, and the growth of xenograft tumors in vivo was markedly inhibited. Functionally, DCBLD2-SE facilitates tumor progression through a DCBLD2-dependent CD146/AKT/TNFRSF6B signaling axis. Clinically, high expression of DCBLD2 correlates with malignant metastasis and poor overall survival in patients with colorectal cancer. In summary, this study uncovers a previously undescribed DCBLD2-centered regulatory cascade that promotes colorectal cancer initiation and progression. DCBLD2-SE and its binding transcription factor activator protein-1 represent promising prognostic biomarkers and actionable therapeutic targets for colorectal cancer.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-tuning the lysine-arginine duet: a dietary approach to suppress tumor growth.","authors":"Ben-Chi Zhao, Xin-Yuan Zhao, Wen-Xiu Li, Xiao Lan, Xiao-Ming Huang, Hao Feng, An-Qi Li, Run-Lu Shi, Hui-Lin Li, Xi Xie, Guo-Hui Wan, Ren-Jie Jiao, Di Chen, Jian-Sheng Kang, Qiao-Ping Wang","doi":"10.1186/s43556-026-00588-0","DOIUrl":"10.1186/s43556-026-00588-0","url":null,"abstract":"<p><p>While dietary therapies targeting individual amino acids in cancer show promise in modulating tumor metabolism, the issue of nutrient competition between tumors and the immune system remains unresolved. The current approaches face significant challenges, particularly in the context of metabolic adaptability and immune responses. Here, we demonstrate that the combined modulation of lysine (Lys) and arginine (Arg) balances tumor suppression and host fitness. Using a cross-species approach combining Drosophila and mouse models, we define a narrow therapeutic window for Lys and Arg. A balanced combination (0.5% Lys/0.5% Arg) reduces tumor burden, extends survival, and preserves host fitness in tumor-bearing mice, whereas an imbalanced formulation (0.25% Lys/1% Arg, LLHA) paradoxically accelerates tumor progression. Single-cell RNA sequencing revealed that LLHA was associated with increased B cells, M1-annotated macrophages and reduced T cells, consistent with systemic immune remodeling that may favor tumor progression, accompanied by decreased Rps6 and Rps29 and increased Hba-a1 and Hbb-bt expression, suggesting alterations in mechanistic target of rapamycin (mTOR), hemoglobin, and ribosomal/translational pathways in immune cells. By defining biphasic thresholds and identifying optimal Lys/Arg combinations, this work provides a preclinical framework for investigating how balanced Lys/Arg modulation may influence tumor control and host fitness. This represents a step towards potential future synergy with immunotherapies, contingent upon further validation of immune dependency.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α1-Antitrypsin attenuates microglial NLR family pyrin domain containing 3 inflammasome activation via cannabinoid receptor 2 signaling to ameliorate α-synucleinopathy-related behavioral deficits.","authors":"Linjuan Feng, Hsuan Lo, Weipin Weng, Jiahao Zheng, Yixin Sun, Wei Lin, Xiaochun Chen, Yanping Wang, Xiaodong Pan","doi":"10.1186/s43556-026-00583-5","DOIUrl":"10.1186/s43556-026-00583-5","url":null,"abstract":"<p><p>α-Synucleinopathies are marked by persistent neuroinflammation and disabling non-motor symptoms involving nucleus accumbens (NAc) dysfunction, yet the neuroimmune mechanisms linking microglial activation to accumbal synaptic pathology remain poorly understood. Here, we identify α1-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in α-syn pathology. An acute transcriptomic screen revealed prominent induction of the Serpina1 gene family, while primary-microglial and chronic AAV-α-syn experiments showed that Cnr2 deficiency amplified Serpina1/AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT-CB2R association under the respective assay conditions. Functionally, AAT reduced the α-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca²⁺ responses, calpain-1 activity, GSK-3β N-terminal cleavage, and NLRP3/caspase-1-related cytokine production; these effects were substantially diminished in Cnr2-deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under Cnr2-deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT-CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in α-synucleinopathies.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian tumor domain-containing protein 1 deficiency attenuates metabolic dysfunction-associated steatotic liver disease by promoting the ubiquitination of HSP90α in hepatocytes.","authors":"Mei-Qin Huang, Si-Yi Wei, Meng-Zhe Li, Tian-Yu Chen, Shu-Qin Ou, Meng Gao, Feng Shi, Tao Zhang, Ying-Lan Liu, Meng-Zhuo Qin, Run-Lei Du, Qi Zhang, Bai-Qi Wang, Xiao-Dong Zhang","doi":"10.1186/s43556-026-00595-1","DOIUrl":"10.1186/s43556-026-00595-1","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet approved pharmacotherapies remain limited. The ovarian tumor domain-containing protein 1 (OTUD1) has been implicated in metabolic regulation, but its role in MASLD remains unclear. OTUD1 expression was significantly elevated in liver samples from patients with MASLD and in high-fat diet (HFD)-fed mice, a finding further supported by two independent Gene Expression Omnibus (GEO) cohorts (GSE24807 and GSE126848). Studies using systemic Otud1-knockout mice showed that Otud1 deficiency markedly alleviated insulin resistance and inflammation under HFD and high-fat, methionine-restricted, choline-deficient (HFMCD) diet conditions. To assess the hepatocyte-specific and therapeutic relevance of OTUD1, Otud1 was silenced in hepatocytes using AAV8-TBG-shOtud1, which significantly ameliorated HFMCD-induced steatohepatitis. Mechanistically, integrated interactome analyses identified heat shock protein 90α (HSP90α) as a direct substrate of OTUD1. OTUD1 bound to HSP90α and removed its K48-linked polyubiquitin chains at K283, thereby preventing its proteasomal degradation and enhancing its stability. This effect was required for OTUD1-driven lipid accumulation in hepatocytes, as the catalytically inactive OTUD1-C320S mutant failed to stabilize HSP90α or promote lipid deposition. Transcriptomic profiling further revealed that OTUD1 overexpression activated lipid metabolism and inflammatory pathways in OA/PA-treated LO2 cells. Together, these findings identify OTUD1 as a previously unrecognized driver of MASLD progression through the OTUD1-HSP90α axis and suggest that OTUD1 may serve as a potential therapeutic target for metabolic liver disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}