Mammalian Genome最新文献

{"title":"Metabolic convergence of diabetes and prostate cancer: from dysglycemia to tumor microenvironment reprogramming.","authors":"Anirban Goutam Mukherjee, Ankit Kumar Bharti, Deepthi Maria Mathew, Abilash Valsala Gopalakrishnan, S Nishu","doi":"10.1007/s00335-026-10274-9","DOIUrl":"https://doi.org/10.1007/s00335-026-10274-9","url":null,"abstract":"<p><p>The relationship between diabetes mellitus and prostate cancer (PC) represents one of the most intriguing paradoxes in cancer epidemiology, with diabetic individuals exhibiting a reduced incidence of PC yet poorer prognosis following diagnosis. This apparent contradiction underscores the need for an integrated understanding of how systemic metabolic dysfunction influences prostate carcinogenesis and disease progression. The present review critically synthesizes contemporary epidemiological, mechanistic, and translational evidence to establish metabolic convergence as a unifying framework linking diabetes-associated metabolic abnormalities with PC biology. Current evidence indicates that chronic dysglycemia, hyperinsulinemia, insulin resistance, and endocrine perturbations orchestrate interconnected intracellular signaling networks involving PI3K-AKT-mTOR, AMPK, AGE-RAGE signaling, oxidative stress, mitochondrial dysfunction, and epigenetic reprogramming, collectively driving metabolic adaptation and tumor evolution. Beyond tumor-intrinsic mechanisms, diabetes profoundly remodels the prostate tumor microenvironment through alterations in stromal metabolism, cancer-associated fibroblast activation, adipocyte-tumor crosstalk, extracellular matrix (ECM) remodeling, hypoxic adaptation, and vascular dysfunction, while simultaneously promoting immunometabolic reprogramming characterized by macrophage polarization, T-cell dysfunction, immune checkpoint activation, and immune evasion. The review further examines the bidirectional interactions between antidiabetic therapies and PC treatment, critically evaluating the translational potential of metformin and emerging glucose-lowering agents within the context of precision metabolic therapeutics. Finally, future directions encompassing biomarker-guided patient stratification, longitudinal metabolic profiling, multi-omics integration, artificial intelligence, and clinically relevant mechanistic validation are discussed as essential components of next-generation precision oncology. Collectively, this review reframes diabetes as an active metabolic determinant of PC rather than a coincidental comorbidity and highlights metabolism-centered precision strategies as promising avenues for improving risk stratification, therapeutic decision-making, and clinical outcomes in diabetes-associated PC.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of miR-141/200c conditional knockout mice from knockout-first, reporter-tagged parent and functional validation of the floxed allele.","authors":"Sanjeev Kumar Yadav, Rashmi Srivastava, Mary-Katherine Cormier, Katie Lowther, Siu-Pok Yee, Rajkumar Verma","doi":"10.1007/s00335-026-10271-y","DOIUrl":"https://doi.org/10.1007/s00335-026-10271-y","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) of the miR-200 family-specifically miR-141 and miR-200c-regulate neurogenesis, differentiation, and epithelial-mesenchymal transitions in development. Dysregulation of these miRNAs is associated with several diseases including cancer and stroke. The Mirc13tm1Mtm/Mmjax mouse line, which targets the miR-141/200c cluster, was originally generated and described by Park et al. 2012 as a knockout-first, reporter-tagged insertion with conditional potential (conditional-ready) mouse line. Harnessing its full potential requires a two-step breeding process: breeding with FLP mice to excise the lacZ/neo cassette, then breeding with Cre to delete the floxed miRNA cluster (Park et al. 2012). However, many studies either bypassed removal of the lacZ/Neo cassettes and treated the mouse line as Mirc13 knockouts or bred directly with Cre mouse lines, which could lead to unpredictable recombination and genotypes. Here we show that retention of the lacZ/Neo cassette is associated with reduced expression of the neighboring genes Ptpn6, Phb2 and Atn1 in the olfactory bulb, and that these genes are expressed normally once the cassette is excised. We therefore recommend a validated two-step FLPo-then-Cre breeding plan for this line, together with case-by-case allele validation for other knockout-first, reporter-tagged mouse lines.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning identifies ac4C-related prognostic signature and TUBA1C as therapeutic target in COAD.","authors":"Baizhi Zhai, Yuxiang Fan, Heng Ma, Xiaowei Xia, Yi Zhao, Jia Lu, Zhihong Zhang, Yi Wang, Bo Wu, Xia Yuan, Zhihui Yu","doi":"10.1007/s00335-026-10267-8","DOIUrl":"10.1007/s00335-026-10267-8","url":null,"abstract":"<p><p>To explore the role of N4-acetylcytidine (ac4C)-related genes (acRGs) in colon adenocarcinoma (COAD) and identify reliable prognostic biomarkers and potential therapeutic targets. Multi-source transcriptomic datasets (TCGA-COAD, GSE39582, GSE17536) and single-cell RNA-seq data were analyzed. Ten machine learning algorithms were integrated to construct an acRG-based prognostic signature (acRGBS). Immune microenvironment (TME) and genomic profiling were performed, with in vitro functional experiments validating TUBA1C's role. acRGBS, comprising four hub genes (SARAF, CDC42SE2, TSPYL2, TUBA1C), effectively stratified COAD patients into high- and low-risk groups with distinct survival outcomes and was an independent prognostic factor. High-risk patients exhibited increased genomic instability and immunosuppressive TME, while low-risk patients had favorable immunotherapy response. TUBA1C was overexpressed in COAD cells, and its knockdown inhibited proliferation/migration and induced apoptosis. The acRGBS is a robust prognostic tool for COAD, and TUBA1C serves as a candidate therapeutic target, providing new insights for personalized COAD management.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long non-coding RNAs link DNA methylation to immune regulatory networks in bovine subclinical mastitis.","authors":"Shraddha Dwivedi, Amit Kumar, Ujjwal Kumar De, Anuj Chauhan, Shivani Khanna, Amritanshu Upadhyay, Diksha Upreti, Bablu Kumar, Girish Kumar Jha, Subodh Kumar","doi":"10.1007/s00335-026-10273-w","DOIUrl":"https://doi.org/10.1007/s00335-026-10273-w","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) are emerging as important regulators of inflammatory and immune signaling, yet their contribution to bovine subclinical mastitis remains poorly defined. Here, we characterized the lncRNA expression landscape associated with disease in milk somatic cells of healthy and subclinical mastitic Vrindavani cattle. We identified 11,403 high-confidence lncRNAs, of which 104 were differentially expressed in subclinical mastitis (adjusted P < 0.05; |log2FC| ≥ 1), with the vast majority upregulated in mastitic samples. Predicted cis- and trans-associated target analyses identified 637 non-redundant genes, and KEGG analysis identified 8 significantly enriched cis-associated pathways and 152 significantly enriched trans-associated pathways (adjusted P < 0.05), predominantly enriched for immune and inflammation-related pathways. These findings prioritized a subset of mastitis-associated lncRNAs for subsequent methylation and interaction-network analyses. A subset of these lncRNAs further overlapped differentially methylated regions (DMRs), suggesting a potential association between lncRNA expression changes and DNA methylation alterations. Integration of lncRNA-miRNA and miRNA-mRNA interactions identified lncRNA-miRNA-mRNA interaction networks involving DMR-associated lncRNAs. Among the prioritized candidates, MSTRG.28878.1 showed overlap with a hypomethylated promoter-associated DMR, increased expression, and multiple connections within the predicted interaction network. Together, these findings identify candidate lncRNAs, methylation-associated loci, and predicted molecular interactions associated with bovine subclinical mastitis and provide a resource for future functional investigation of candidate non-coding RNA-associated mechanisms in disease.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing the genetic legacy of Malabari goats through complete mitogenome sequencing: evidence of maritime exchange via the historic spice route.","authors":"M R Akhila, Marykutty Thomas, Jinty Sukumaran, P M Rojan, J Saalom King, R Thirupathy Venkatachalapathy, K A Bindu","doi":"10.1007/s00335-026-10269-6","DOIUrl":"https://doi.org/10.1007/s00335-026-10269-6","url":null,"abstract":"<p><p>The Malabari goat of South India is one of the most efficient dual-purpose breeds, exhibiting exceptional adaptability to humid tropical stressors. This study aimed to characterize the complete mitochondrial genome of Malabari goats and to decipher their maternal phylogenetic relationships, thereby providing insights into lineage divergence, domestication origins and genetic connectivity with global caprine populations. Whole-genome sequencing of pooled DNA from 20 unrelated Malabari goats revealed a complete mitogenome comprising 37 genes, including 22 transfer RNAs (tRNAs), 13 protein-coding genes (PCGs) and two ribosomal RNAs (rRNAs), in addition to a hypervariable non-coding displacement loop (D-loop) region. A total of 45 single nucleotide polymorphisms (SNPs) and two indels were identified, of which 21 SNPs were detected in PCGs-six of them non-synonymous. Importantly, we report the first tRNA mutation described in goats: a novel heteroplasmic substitution (11693 T>C) in the MT-TL2 gene coding for tRNA^LeuCUN. The mitochondrial genome analysis of Malabari goats revealed their closest genetic affinity with Iraqi Meriz goats and Arabian goat populations, highlighting significant maternal contributions via ancient maritime trade networks, distinct from most Indian breeds that predominantly belong to haplogroup A. The whole mitogenome phylogenetic analysis revealed that Malabari goats cluster in a monophyletic group together with local goats from Vietnam, domestic goats from Malaysia and domestic goats from Russia. Phylogenetic reconstruction based on mitochondrial D-loop placed Malabari goats within haplogroup B1 along with goats from Iraq, Oman and Gujarat in India. Mitogenome analysis of Malabari goats provides genetic evidence of their genetic roots shaped by maritime exchanges along the ancient Spice Route.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a metastasis-associated prognostic gene signature in osteosarcoma through integrated bioinformatics and functional analysis.","authors":"Qingquan Xia, Xiangchao Meng, Xuhua Wu, Xujun Li, Teng Fei, Ke Rong","doi":"10.1007/s00335-026-10272-x","DOIUrl":"https://doi.org/10.1007/s00335-026-10272-x","url":null,"abstract":"<p><p>Osteosarcoma is a highly aggressive bone malignancy with a strong tendency for metastasis and poor clinical outcomes. The molecular mechanisms driving osteosarcoma progression and metastasis remain incompletely understood, highlighting the need to identify robust biomarkers and therapeutic targets. Weighted gene co-expression network analysis (WGCNA) was performed using osteosarcoma datasets from the Gene Expression Omnibus to identify metastasis-associated gene modules and hub genes. Expression, methylation, mutation, immune infiltration, and drug sensitivity analyses were conducted using multiple public databases, including TCGA, GSCA, UALCAN, and cBioPortal. A prognostic model was developed using the TARGET osteosarcoma cohort and validated in an independent GEO dataset. Functional roles of hub genes were investigated through loss- and gain-of-function experiments in sarcoma cell lines using RT-qPCR, Western blotting, proliferation, colony formation, wound-healing, and luciferase reporter assays. Four hub genes, AURKB, CDC20, KIF11, and TOP2A, were identified as strongly associated with metastasis. These genes were significantly upregulated in sarcoma tissues and cell lines and demonstrated excellent diagnostic performance. Promoter hypomethylation and frequent genomic alterations contributed to their aberrant expression. High expression of the hub genes was associated with poor overall survival, and a four-gene prognostic model showed strong predictive performance in both training and validation cohorts. Functional assays confirmed that these genes promote sarcoma cell proliferation and migration, while miRNA-mediated regulation and drug resistance associations further highlighted their biological relevance. This integrated computational and experimental study identifies AURKB, CDC20, KIF11, and TOP2A as key oncogenic drivers in osteosarcoma, with significant diagnostic, prognostic, and therapeutic implications.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of auditory and vestibular function and gene therapy in the Snell's waltzer mouse model of human deafness and balance dysfunction.","authors":"Eyal Marton, Roni Hahn, Lior Bikovski, Gwenaëlle S G Géléoc, Jeffrey R Holt, Matti Mintz, Karen B Avraham","doi":"10.1007/s00335-026-10263-y","DOIUrl":"10.1007/s00335-026-10263-y","url":null,"abstract":"<p><p>The Snell's waltzer mouse (Myo6^sv/sv) serves as a model for human deafness and vestibular behavioral impairment, caused by a spontaneous 130 bp recessive deletion in the Myo6 gene. In this study, we characterized the auditory and vestibular phenotypes of Myo6^sv/sv mice. These mice exhibit profound hearing loss, with cochlear hair cell stereocilia beginning to fuse soon after birth, ultimately leading to disorganization of hair bundles and degeneration of hair cells. Mice also exhibit behavioral phenotypes characterized by severe imbalance, hyperactivity with bouts of circling, and delayed spatial learning of a novel environment, but preserved normal behavioral circadian rhythms. These behaviors emerge in association with the loss of the characteristic staircase morphology of vestibular hair cell stereocilia soon after birth and the subsequent profound elongation of the stereocilia. Adeno-associated virus (AAV) gene replacement therapy, delivered on the day of birth or one day after, failed to restore auditory or vestibular function. Our findings underscore the essential role of Myo6 in the auditory and vestibular systems and imply prenatal intervention may be required for effective therapy.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics integration and machine learning define an iron-sulfur cluster/zinc-binding protein prognostic signature in esophageal squamous cell carcinoma.","authors":"Wenhuan Chen, Tongtong Chen, Zhixuan Li, Wan Lin, Zefeng Xie, Hansheng Wu, Liyan Xu, Enmin Li, Hefeng Zhang, Yinwei Cheng","doi":"10.1007/s00335-026-10270-z","DOIUrl":"https://doi.org/10.1007/s00335-026-10270-z","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) is characterized by substantial intratumoral heterogeneity and poor clinical prognosis. Although metalloproteins are well-documented to drive ESCC malignant progression, incomplete functional annotation of this protein family significantly impedes the clinical translation of related research outcomes. This study reports the development and validation of a reliable prognostic model via integrating AlphaFold2-predicted iron-Sulfur (Fe-S) Cluster/Zinc (Zn)-binding proteins with ESCC multi-omics data. Nine differentially expressed AlphaFold2-predicted Fe-S/Zn-binding proteins significantly associated with ESCC prognosis were identified through integrated analysis of multi-omics and clinical data from public datasets and independent ESCC cohorts. After systematic evaluation of 117 machine learning combinations, a three-Fe-S/Zn-binding protein Prognostic Signature (FZPS) comprising YPEL5, MIB1 and ELAC2 was constructed, and validated as an independent predictor of poor overall survival across cohorts. High FZPS risk correlates with an immune-excluded, stress-adaptive phenotype with p21-driven inflammation and intrinsic immunotherapy resistance, while low-FZPS tumors harbor more actionable mutations and exhibit enhanced sensitivity to targeted therapy and immunotherapy. In vitro assays confirmed YPEL5 knockdown markedly suppresses ESCC cell viability, proliferation and migration. In conclusion, FZPS is a reliable independent prognostic biomarker guiding precision oncology practice for ESCC.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide characterization of copy number variations in Nagami Mithun (Bos frontalis) using whole-genome resequencing.","authors":"Bendangkokba Kichu, Harshit Kumar, Rajkrishna Mondal, Kuluve Chotso, J K Chamuah, S S Hanah, Girish Patil Shivanagowda","doi":"10.1007/s00335-026-10268-7","DOIUrl":"https://doi.org/10.1007/s00335-026-10268-7","url":null,"abstract":"<p><p>Copy number variations (CNVs) represent an important source of structural genomic variation contributing to genomic diversity in livestock species. The Nagami Mithun (Bos frontalis), a semi-domesticated bovid indigenous to the forested hill regions of Northeast India, remains poorly characterized at the level of genome structural variation. In this study, whole-genome resequencing data from 12 Nagami Mithun individuals were analyzed to establish the first genome-wide copy number variation (CNV) map for this indigenous population. After quality filtering and alignment to the Bos taurus ARS-UCD2.0 reference genome, CNVs were detected using the read-depth-based tool CNVnator v0.4.1 with stringent filtering criteria (e-value < 0.05, q0 < 0.5, length > 1 kb). A total of 7273 CNVs were identified, including 5005 deletions (68.8%) and 2,268 duplications (31.2%), which were subsequently integrated into 1135 CNV regions (CNVRs). Population-level integration of individual CNVs resulted in 1135 CNVRs spanning approximately 173.4 Mb of the autosomal genome. Functional annotations identified 2281 genes overlapping CNVRs. Gene Ontology enrichment analysis identified overrepresentation of genes annotated to chemosensory perception, immune-related processes, and amino-acid transport functions, while KEGG pathway analysis identified enrichment of pathways annotated as natural killer cell-mediated cytotoxicity and antigen processing and presentation. CNV-QTL overlap analysis identified hypothesis-generating candidate genomic regions harboring genes (e.g., AFF2, EDA, COL4A5, TRPC5) that are associated with production, reproduction, and conformation traits in bovines, representing putative positional overlaps requiring future validation in Mithun populations. This study provides a foundational structural variation resource for future comparative, conservation, and functional genomic studies in Mithun. These findings provide a valuable genomic resource for future marker-assisted selection, comparative genomics, and conservation breeding programs aimed at preserving Nagami Mithun populations.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZDHHC5 may regulate the function of NKT cells and the immune response in Meniere's disease.","authors":"Ruilong Li, Keguang Chen","doi":"10.1007/s00335-026-10264-x","DOIUrl":"https://doi.org/10.1007/s00335-026-10264-x","url":null,"abstract":"<p><p>Meniere's disease (MD) is a heterogeneous, rare inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Its molecular mechanisms remain unclear due to significant clinical and immunological heterogeneity. In this study, we integrated multi‑omics genetic data to systematically screen for palmitoylation regulatory genes associated with MD risk. We first intersected 31 core palmitoylation genes with blood cis‑eQTL datasets to identify candidate expression‑related genes, then performed two‑sample Mendelian randomization (MR) to examine their genetic correlation with MD. Summary‑data‑based MR (SMR) using two independent peripheral blood eQTL cohorts (eQTLGen and GTEx) was further applied to validate robust candidate genes. Two‑sample inverse‑variance weighted (IVW) MR revealed nominally significant associations between PPT2, ZDHHC18, ZDHHC5 and MD risk. Independent SMR validation confirmed that peripheral ZDHHC5 expression was significantly correlated with MD (eQTLGen: PSMR = 0.023; GTEx: PSMR = 0.006), and a non‑significant HEIDI test ruled out strong linkage disequilibrium confounding. We further explored potential immune mediators using a two‑step MR screening framework covering 731 peripheral immune cell phenotypes. After Benjamini-Hochberg false discovery rate (FDR) correction for all immune traits to control for multiple testing, no immune cell phenotype retained an FDR < 0.05 association with MD; therefore, formal mediation analysis was not conducted. In summary, this MR‑based genetic analysis identifies ZDHHC5 as a gene associated with MD susceptibility. The potential immune regulatory axis involving NKT cells remains speculative and requires validation through large‑scale stratified immune cohort data and functional cellular/animal experiments. No definitive causal or therapeutic conclusions can be drawn from the present genetic statistical evidence alone.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}