Journal of Translational Medicine最新文献

{"title":"Neutrophil extracellular trapping network-associated biomarkers in liver fibrosis: machine learning and experimental validation.","authors":"Yanbo Li, Yanping Lu, Bohao Huang, Chao Lei, Qingjuan Wu, Jiuchong Wang","doi":"10.1186/s12967-025-06819-2","DOIUrl":"10.1186/s12967-025-06819-2","url":null,"abstract":"<p><strong>Background: </strong>The diagnostic and therapeutic potential of neutrophil extracellular traps (NETs) in liver fibrosis (LF) has not been fully explored. We aim to screen and verify NETs-related liver fibrosis biomarkers through machine learning.</p><p><strong>Methods: </strong>In order to obtain NETs-related differentially expressed genes (NETs-DEGs), differential analysis and WGCNA analysis were performed on the GEO dataset (GSE84044, GSE49541) and the NETs dataset. Enrichment analysis and protein interaction analysis were used to reveal the candidate genes and potential mechanisms of NETs-related liver fibrosis. Biomarkers were screened using SVM-RFE and Boruta machine learning algorithms, followed by immune infiltration analysis. A multi-stage model of fibrosis in mice was constructed, and neutrophil infiltration, NETs accumulation and NETs-related biomarkers were characterized by immunohistochemistry, immunofluorescence, flow cytometry and qPCR. Finally, the molecular regulatory network and potential drugs of biomarkers were predicted.</p><p><strong>Results: </strong>A total of 166 NETs-DEGs were identified. Through enrichment analysis, these genes were mainly enriched in chemokine signaling pathway and cytokine-cytokine receptor interaction pathway. Machine learning screened CCL2 as a NETs-related liver fibrosis biomarker, involved in ribosome-related processes, cell cycle regulation and allograft rejection pathways. Immune infiltration analysis showed that there were significant differences in 22 immune cell subtypes between fibrotic samples and healthy samples, including neutrophils mainly related to NETs production. The results of in vivo experiments showed that neutrophil infiltration, NETs accumulation and CCL2 level were up-regulated during fibrosis. A total of 5 miRNAs, 2 lncRNAs, 20 function-related genes and 6 potential drugs were identified based on CCL2.</p><p><strong>Conclusions: </strong>This study identified CCL2 as a biomarker for nets-related liver fibrosis, providing a new perspective for understanding the mechanisms of nets-mediated fibrosis and promoting therapeutic discovery.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1058"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental endocrine function is controlled by maternal gut Bifidobacterium in germ-free mice.","authors":"Jorge Lopez-Tello, Raymond Kiu, Zoe Schofield, Matthew J Dalby, Douwe van Sinderen, Gwénaëlle Le Gall, Lindsay J Hall, Amanda N Sferruzzi-Perri","doi":"10.1186/s12967-025-07198-4","DOIUrl":"10.1186/s12967-025-07198-4","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have shown that the maternal gut microbiota can regulate placental growth, particularly the transport region, in association with fetal growth. However, the specific role of certain microorganisms in modulating the hormonal production of the placenta, which is critical for supporting fetal development and maintaining a healthy pregnancy, remains largely unexplored. In this context, the objective of this study is to determine whether the maternal colonisation with the early life gut bacterium Bifidobacterium breve UCC2003 regulates placental endocrine function.</p><p><strong>Methods: </strong>Pregnant germ-free mice were colonized with or without Bifidobacterium breve UCC2003 (BIF) during pregnancy. The endocrine region of the placenta (junctional zone, Jz) was collected to assess its metabolic profile using metabolomics, the expression of key nutrient uptake genes, hormones and synthetic genes by qPCR, and proteome using LC-MS/MS.</p><p><strong>Results: </strong>BIF colonised dams had increased lactate and taurine concentrations in the placental Jz. BIF presence was also associated with upregulated expression of nutrient carriers, particularly those involved in large neutral amino acid and monocarboxylate uptake (e.g., Slc7a8 and Slc16a4). Additionally, key hormones, such as prolactins and pregnancy-specific glycoproteins, were upregulated. The Jz proteome was changed in BIF colonised dams, with over 400 proteins dysregulated. Pathway analysis revealed more than 150 biological processes were altered, including transcriptional activity, protein synthesis, cell cycle progression, and metabolic regulation. Proteins regulated by BIF in the placental Jz were correlated with fetal growth and nutrient levels (namely glucose). Notably, maternal-associated BIF reduced the number of fetal resorptions (early fetal loss).</p><p><strong>Conclusions: </strong>In germ-free mice, maternal-associated gut Bifidobacterium breve UCC2003 regulates placental endocrine capacity, by altering its metabolic profile and ability to produce endocrine factors. This study provides the first clear evidence that the maternal gut microbiota not only influences placental transport function, but also regulates its endocrine outputs.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1031"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hispidulin suppresses osteosarcoma by directly targeting FABP4 to disrupt lipid metabolism and inhibit the PI3K/AKT pathway.","authors":"Xuhui Yuan, Shaolin Yu, Zhengxing Zeng, Liren Yi, Bo Yu, Lingxiao Zhu","doi":"10.1186/s12967-025-07128-4","DOIUrl":"10.1186/s12967-025-07128-4","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS), a prevalent primary bone malignancy, has a dismal prognosis in metastatic cases (5-year survival < 30%), highlighting the need for novel therapies. Hispidulin (HIS), a natural flavonoid, shows anticancer potential, but its precise mechanism and direct target in OS are uncharacterized.</p><p><strong>Purpose: </strong>This study aimed to delineate HIS's anti-neoplastic mechanisms in OS, focusing on its impact on lipid metabolism, associated signaling, and its direct molecular target.</p><p><strong>Methods: </strong>In vitro anti-tumor effects of HIS were assessed (CCK-8, colony formation, Transwell, flow cytometry). RNA sequencing and molecular docking identified regulatory pathways and targets. Western blotting, lipid metabolism assays, and rescue experiments explored mechanisms. In vivo efficacy was evaluated using xenografts.</p><p><strong>Results: </strong>HIS potently inhibited OS cell proliferation, colony formation, migration, and invasion, with minimal toxicity to normal osteoblasts. It induced G2/M arrest and apoptosis. HIS directly targeted Fatty Acid Binding Protein 4 (FABP4), modulating lipid metabolism and subsequently inhibiting the PI3K/AKT pathway. This reduced intracellular free fatty acids and fatty acid synthase activity. FABP4 overexpression abrogated HIS's anti-tumor effects. In vivo, HIS impeded tumor growth and reduced Ki67 and FABP4 expression.</p><p><strong>Conclusion: </strong>Hispidulin exerts robust anti-tumor activity in OS by directly targeting FABP4, thereby disrupting lipid metabolism and suppressing the oncogenic PI3K/AKT cascade. HIS is a highly encouraging therapeutic candidate for OS.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1062"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression.","authors":"Cheng Dai, Bin Shen, Shenyan Liu, Cong Li, Shuqun Yang, Jie Wang, Jie Zhang, Manqi Liu, Zhixuan Zhu, Wan Shi, Qi Zhang, Zhui Chen, Nannan Zhang","doi":"10.1186/s12967-025-07235-2","DOIUrl":"10.1186/s12967-025-07235-2","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1063"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics as an emerging driver of osteoarthritis: a translational synthesis of environmental exposure, patho-mechanisms, and public health implications.","authors":"Muhammad Adil Malik, Song Wu, Wenxiu Zhang, Junjie Huang, Xu Cao, Uroosa Ayub, Adnan Malik","doi":"10.1186/s12967-025-07081-2","DOIUrl":"10.1186/s12967-025-07081-2","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA), a leading global cause of disability, has been increasingly associated with environmental microplastic (MP) exposure. MPs bioaccumulate in human tissues via the food chain and may disrupt joint homeostasis through inflammatory and oxidative pathways. However, their role in OA pathogenesis remains underexplored in translational contexts.</p><p><strong>Methods: </strong>We conducted a synthesis of environmental microplastic contamination data from global aquatic ecosystems, integrated with molecular pathway analyses and epidemiological evidence. Microplastic sampling and polymer identification were performed using GPS mapping, stereomicroscopy, and Fourier-transform infrared (FTIR) spectroscopy. Public health implications were assessed through cost-effectiveness analyses of MP mitigation strategies.</p><p><strong>Results: </strong>High MP exposure regions demonstrated elevated OA prevalence, with MPs identified in cartilage and skeletal tissues. Mechanistically, MPs activated NLRP3 inflammasomes, induced reactive oxygen species (ROS), and disrupted osteoblast/osteoclast balance. Epidemiological data revealed that populations in coastal and industrial regions exhibited up to 1.85-fold increased OA risk. Cost-benefit modeling indicated that MP reduction strategies, such as seafood safety regulations and advanced water filtration, could yield annual healthcare savings exceeding $50 billion globally.</p><p><strong>Conclusions: </strong>Microplastics constitute an emerging and modifiable environmental risk factor for OA. Translational strategies targeting MP reduction may mitigate OA burden and offer substantial public health and economic benefits. This underscores the need for integrated environmental-health policies and further clinical investigation.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1061"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amide proton transfer imaging reveals cerebral metabolic alterations associated with cognitive impairment in type 2 diabetes mellitus.","authors":"Hongjun Jiang, Shuncheng Yu, Langxuan Yu, Wei Du, Chang Yuan, Jiajun Cao, Qingwei Song, Tieli Liu, Yanwei Miao, Weiwei Wang","doi":"10.1186/s12967-025-07083-0","DOIUrl":"10.1186/s12967-025-07083-0","url":null,"abstract":"<p><strong>Background: </strong>Amide proton transfer (APT) imaging indirectly reflects tissue metabolic changes by detecting variations in the concentration of mobile amide protons and tissue pH. Type 2 diabetes mellitus (T2DM) is often accompanied by cognitive dysfunction and diabetic encephalopathy, both of which pose serious threat to human health and quality of life. This study aimed to evaluate the potential of APT imaging as a novel biomarker for detecting cerebral metabolic alterations and to investigate its associations with cognitive impairment in patients with T2DM.</p><p><strong>Methods: </strong>This study included 32 T2DM patients, comprising 16 with mild cognitive impairment (MCI) and 16 with normal cognition (NC), and 26 healthy controls. Clinical data and cognitive assessments were collected within one week of MRI acquisition. Imaging markers of cerebral small vessel disease (CSVD) were evaluated using AI-assisted tools. APT values were measured in predefined brain regions, including the hippocampus (hipp), temporal white matter (TWM), temporal gray matter (TGM), occipital white matter (OWM), occipital gray matter (OGM), and cerebral peduncles (CPs) using 3D Slicer software. Group differences were analyzed with one-way ANOVA followed by Bonferroni-corrected post hoc tests (or Kruskal-Wallis test with Bonferroni correction for non-parametric data). Partial correlations (Bonferroni-corrected) assessed the links between APT values and cognitive scores, as well as between APT values and CSVD imaging markers.</p><p><strong>Results: </strong>The APT values of the left temporal white matter (TWM) and the right temporal gray matter (TGM) were significantly different among the three groups. Among them, the APT values of T2DM-MCI group were significantly lower. In T2DM patients, partial correlation analysis showed that the APT values of the left TWM was positively correlated with MMSE attention and calculation score, MoCA attention score, and the number of lacunar infarcts (LI), and negatively correlated with the severity of white matter hyperintensities (WMH). The APT values of right TGM was positively correlated with MoCA total scores, MoCA visuospatial scores and MoCA delayed recall scores.</p><p><strong>Conclusion: </strong>T2DM patients with mild cognitive impairment exhibited significantly lower APT values in the left temporal white matter and right temporal gray matter. These lower APT values were strongly associated with poorer cognitive performance and more severe CSVD. APT imaging may serve as a sensitive, noninvasive biomarker for detecting cerebral metabolic deterioration underlying diabetic cognitive decline.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1059"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Predictive models for live birth outcomes following fresh embryo transfer in assisted reproductive technologies using machine learning.","authors":"Shengnan Wu, Xinbo Wang, Yuechen Liu, Yongyong Ren, Mei Zhao, Haitao Song, Hao Shen, Yueting Wu, Zhiyun Wei, Hui Lu, Kunming Li","doi":"10.1186/s12967-025-07248-x","DOIUrl":"10.1186/s12967-025-07248-x","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1064"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversing coma by senolytics and stem cells: the future is now.","authors":"Thomas E Ichim, Roman A Ramos, Armin Rath, Joel Castellano, Nassir Azimi, James D Veltmeyer, Michael Koumjian, Nicole E Ma, Anil Bajnath, Emma Lin, Gloria E Ichim, Erik J Woods, Jennifer Jothen, Boris N Reznik","doi":"10.1186/s12967-025-07099-6","DOIUrl":"10.1186/s12967-025-07099-6","url":null,"abstract":"<p><p>Global cerebral ischemia (GCI) caused by impaired blood flow to the brain-typically following cardiac arrest or traumatic brain injury-remains the leading cause of coma and disorders of consciousness (DoC). In certain cases, the recovery potential of these patients may be significantly underestimated. Historically, these patients were often given little hope for recovery, particularly due to longstanding, outdated dogmatic views such as the presumed absence of adult neurogenesis. However, recent advances suggest that we have been discounting ongoing mental activity in comatose patients; additionally, emerging evidence shows that some patients in coma retain the capacity for communication through non-traditional means. The authors believe that the exponential progress in the field and the increase of our understanding in neurophysiology, regenerative medicine, and the biology of cellular senescence now makes it plausible to initiate experimental interventions that offer a realistic chance of reversing disorders of consciousness. The proposed strategy involves a two-step therapeutic paradigm: first the use of senolytic approaches to remove senescent cells and reduce neuroinflammatory burden (\"clear the debris\"); second, stimulation of neural regeneration through stem cell therapies, combined with electrophysiologic/pharmacological stimulation. The authors propose, that this integrated approach offers a novel treatment paradigm to address the previously insurmountable challenge of coma reversal.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1060"},"PeriodicalIF":7.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topical application of a placental mesenchymal stem cell-embedded biomaterial hydrogel accelerates the repair of radiation-induced skin damage: a double-blind randomized phase II clinical trial.","authors":"Linghan Tian, Zhibo Han, Ming Jiang, Yi Yang, Yunhe Ju, Ming Zhang, Yan Chen, Iaming Gu, Ying Song, Lei Bao, Qian Song, Lu Yuan, Zongjin Li, Jundong Gu, Zhongchao Han, Jian Dong","doi":"10.1186/s12967-025-07060-7","DOIUrl":"10.1186/s12967-025-07060-7","url":null,"abstract":"<p><strong>Background: </strong>Radiation-induced skin injury (RSI) is a common complication of radiation therapy, that severely reduces the quality of life of patients, and there is currently no gold standard for treatment. Placental mesenchymal stem cells (PMSCs) have emerged as a promising therapeutic approach due to their regenerative and anti-inflammatory properties, and biomaterials can serve as cell scaffolds to prolong cell survival time. This study is the first to evaluate the safety and efficacy of the a topical application of PMSCs-embedded alginate hydrogel (PMSCs gel) in cancer patients suffering from RSI.</p><p><strong>Materials and methods: </strong>This study was a double-blind, randomized, placebo-controlled phase II clinical trial conducted at Yunnan Cancer Hospital (Chinese Clinical Trial Registry, Approval Number: ChiCTR2400094739) involving participants with grade II or higher radiation-induced skin injuries. The participants were randomly assigned to either the PMSCs gel treatment group or the placebo control group and treated topically for six consecutive days. The primary outcomes included skin injury grade, pain assessment and wound healing rate, whereas the secondary outcomes focused on biomarker changes and quality of life assessments. Statistical analyses were performed using intention-to-treat (ITT) principles.</p><p><strong>Results: </strong>This study included 66 patients, 23 males, and 43 females, with a mean radiation-induced skin injury area of 779 mm². Compared with the placebo control group, the PMSCs gel treatment group presented a faster overall recovery rate compared to the placebo control group, with statistically significant daily improvements from Day 1 to Day 6. Although there was no significant difference in the full healing rates between the groups, the PMSCs gel treatment significantly prevented further wound expansion from Day 2 to Day 6. Moreover, overall pain relief was greater in the PMSCs gel treatment group than in the control group.</p><p><strong>Conclusions: </strong>Our study has demonstrated for the first time that PMSCs hydrogel have significant potential for accelerating the repair of radiation-induced skin damage and reducing skin pain.</p><p><strong>Trial registration: </strong>This retrospectively registered Chinese Clinical Trial Registry identifier: ChiCTR2400094739 ( https://www.chictr.org.cn/bin/project/edit?pid=250420 ).</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1057"},"PeriodicalIF":7.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish.","authors":"Chunyan Xian, Qing Luo, Weiping Li, Lin Zou, Jinbo Liu","doi":"10.1186/s12967-025-07032-x","DOIUrl":"10.1186/s12967-025-07032-x","url":null,"abstract":"<p><strong>Background: </strong>The ATP synthase F1 subunit α (ATP5F1A) gene encodes a critical structural subunit of mitochondrial complex V. ATP5F1A mutations are linked to mitochondrial complex V deficiency diseases. Although only 14 cases have been reported globally, the genotype-phenotype correlations and underlying molecular mechanisms remain poorly understood.</p><p><strong>Objective: </strong>To investigate the pathogenic mechanisms of ATP5F1A deficiency through functional analysis of a recurrent missense variant.</p><p><strong>Method: </strong>A Han Chinese family with developmental delay and motor dysfunction was studied. Whole-exome sequencing and trio analysis identified the causative variant. Pathogenicity was evaluated using bioinformatic predictions and structural modeling. HEK293T cells were transfected with wild-type or mutant-type ATP5F1A plasmids for Western blot and immunofluorescence analysis. Morpholino (MO) oligonucleotides were microinjected into zebrafish embryos for gene knockdown. Motor neuron development was observed in Tg(mnx1:eGFP) zebrafish, with accompanying behavioral assessments. RNA sequencing was conducted to explore the underlying molecular pathways.</p><p><strong>Results: </strong>A de novo missense variant (c.1252G > A, p.Gly418Arg) in ATP5F1A was identified and shown to segregate with the disease phenotype. The mutation reduced protein stability and expression. In HEK293T cells, the mutant protein exhibited reduced expression without affecting mitochondrial localization. In zebrafish, atp5fa1 knockdown caused growth retardation, motor dysfunction, and impaired motor neuron axon development. Rescue experiments with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Transcriptomic analysis identified 2,261 differentially expressed genes, enriched in neurotransmission and apelin signaling pathways. qPCR confirmed downregulation of autophagy-related genes (apln, becn1, map1lc3b) in knockdown larvae. Western blot showed that atp5fa1 knockdown increased P62 and decreased Lc3b-II expression in zebrafish models.</p><p><strong>Conclusion: </strong>This study is the first to report pathogenic ATP5F1A mutations in the Chinese population. Atp5fa1 dysfunction leads to multi-system defects and disease phenotypes in a zebrafish model, possibly mediated through inhibiting autophagy activation mechanisms.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1054"},"PeriodicalIF":7.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}