Mammalian Genome最新文献

{"title":"Genome-wide DAPC-based genetic structure, linkage disequilibrium, and effective population size in indigenous buffaloes of Northeastern and Central India.","authors":"Swati Rulyan, Udayabanu Malairaman, R K Vijh","doi":"10.1007/s00335-026-10240-5","DOIUrl":"10.1007/s00335-026-10240-5","url":null,"abstract":"<p><p>The Indian buffalo population makes a significant component of rural livelihood and dairy economics and has different genetic makeup from the diverse evolutionary processes. The purpose of this study is to determine the amount of genomic variation, linkage disequilibrium (LD), and effective population size (Ne) and genetic relationship of seven buffalo populations living in the Northeast of India and nearby areas by using high-density SNP array. Our study included 327 animals that represented Tripura (n = 53), Meghalaya (n = 43), Manipuri (n = 23), Luit (n = 126), Kalahandi (n = 24), Chilika (n = 36), and Chhattisgarhi (n = 22) populations was genotyped and 621,789 high quality SNPs were obtained after strict quality control filtering. DAPC, pairwise FST, and PCA analyses of population structure showed that the populations were moderately defined by genetic groups. DAPC differentiated clusters which were consistent with patterns of shared ancestry, and there was low to middle differentiation as indicated by FST, especially between populations of Chhattisgarhi, Chilika, Kalahandi, and Meghalaya. The relationships were also supported by PCA that exhibited overlapping and distinct patterns of groups that portrayed the genomic structure. The process of estimating genome-wide linkage disequilibrium involved the utilization of 20 kb intermaker distance bins that range between 10 and 250 kb. Tripura, Manipuri and Chilika buffalo population had a relatively greater LD in the majority of the distance classes, when compared to Luit and Meghalaya which had a more rapid LD decay. It is expected that these trends are manifested by variations in recombination and demographic processes in the past, and not necessarily because of inbreeding itself. Recent Ne estimates for Ne in Manipuri and Tripura were lower, whereas the Ne in Meghalaya, Luit, and Kalahandi was relatively high indicating relatively stable demographic histories. These findings generally describe the population of northeastern Indian buffalos at the genome-wide scale and offer baseline data regarding conservation and breeding goals that would preserve genetic diversity in the long run.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982352","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":"Genomic structural equation modeling reveals the shared genetic architecture of osteosarcopenia across five musculoskeletal phenotypes.","authors":"Weiqiang Lai, Kaiqin Gong, Ronghao Zhong, Weicong Yin, Xu Li, Xinhuang He, Siyuan Hu, Chuqun Chen, Kunrui He, Chunhan Sun, Jianping Zheng, Guowei Zeng","doi":"10.1007/s00335-026-10245-0","DOIUrl":"10.1007/s00335-026-10245-0","url":null,"abstract":"<p><p>Osteosarcopenia-the concurrent presence of osteoporosis and sarcopenia-affects approximately 18.5% of older adults globally, yet its shared genetic basis remains poorly understood. We applied genomic structural equation modeling (Genomic SEM) to integrate genome-wide association study (GWAS) summary statistics across five phenotypes spanning the pathophysiological spectrum of osteosarcopenia: appendicular lean mass (ALM), bone mineral density (BMD), handgrip strength (HGS), walking pace, and fracture. Fine-mapping, transcriptome-wide association study (TWAS), pathway enrichment, cell-type enrichment, and spatial transcriptomic mapping were performed to functionally annotate the identified loci. A single-factor model (CFI = 0.976) captured the shared genetic liability, with HGS and ALM loading most strongly. A two-factor sensitivity analysis confirmed partial separability of muscle and bone dimensions, though the single common factor was retained for integrated downstream annotation. We identified 58,696 genome-wide significant single-nucleotide polymorphisms (SNPs) condensed into 1078 independent lead variants, including 29 novel loci. Fine-mapping prioritized 317 high-confidence causal variants, encompassing key genes including BMP6, ACAN, IHH, LRP5, and SOX5. TWAS and MAGMA converged on IGF1R, FOXO3, and IRS1 as dual susceptibility genes. Pathway analysis revealed significant enrichment in endochondral ossification and growth hormone/insulin-like growth factor-1 signaling. Cell-type enrichment localized genetic risk to mesenchymal stem cells and skeletal muscle satellite cells, while spatial mapping identified cartilage primordium as the most enriched developmental context. This study systematically elucidates the shared genetic architecture of osteosarcopenia, highlighting developmental, endocrine, and stem cell-related pathways as core mediators. These findings provide a theoretical foundation for precision geroscience and the development of dual-target therapeutic strategies.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982261","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":"THBS1: a biomarker for PCOS and its role in pathogenesis via the PI3K/AKT signaling pathway.","authors":"Jie Zhang, Luhongyuan Jin, Chi Chi, Wenjie Hou, Jinhua Zhou","doi":"10.1007/s00335-026-10237-0","DOIUrl":"10.1007/s00335-026-10237-0","url":null,"abstract":"<p><p>This study identified thrombospondin-1 (THBS1) as a potential biomarker for polycystic ovary syndrome (PCOS) and its pivotal role in disease pathogenesis through multi-level bioinformatics analysis and experimental validation. By integrating five PCOS-related datasets and applying multiple machine learning techniques, THBS1 was identified as the most specific differentially expressed gene. Clinical sample analysis confirmed significantly elevated THBS1 levels in PCOS patients (p < 0.0001). In DHEA-induced PCOS cell and animal models, THBS1 upregulation was accompanied by marked suppression of PI3K/AKT signaling pathway activity. THBS1 knockdown significantly restored PI3K/AKT pathway activity in PCOS cells, indicating THBS1 participates in PCOS pathogenesis by negatively regulating this pathway. Animal experiments corroborated in vitro findings, revealing increased THBS1 expression and reduced PI3K/AKT pathway activity in ovarian tissues of PCOS model rats. Molecular docking studies predicted strong binding affinity between pioglitazone hydrochloride and THBS1, suggesting novel therapeutic approaches. This study systematically elucidates for the first time the pivotal role of the THBS1/PI3K/AKT axis in PCOS pathogenesis, providing novel molecular targets and a theoretical foundation for precision diagnosis and personalized treatment. NEW AND NOTEWORTHY: This study systematically demonstrates for the first time the value of THBS1 as a potential biomarker for PCOS. Through multi-level analysis, it confirms that THBS1 participates in the pathogenesis of PCOS by negatively regulating the PI3K/AKT signaling pathway, providing new molecular targets and a theoretical foundation for precise diagnosis and personalized treatment.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982291","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":"Combined single-cell RNA sequencing and mendelian randomization to identify biomarkers associated with circadian rhythm in sarcopenia.","authors":"Yuli Huang, Lifeng Tang, Daoyuan Li, Long Chen, Wenjuan Wu, Dingcheng Zeng, Yanbiao Zhong, Maoyuan Wang","doi":"10.1007/s00335-026-10231-6","DOIUrl":"10.1007/s00335-026-10231-6","url":null,"abstract":"<p><p>Sarcopenia refers to the involuntary loss of skeletal muscle mass and function with aging and is associated with multiple adverse health outcomes. Disruption of normal circadian rhythms due to shift work or nocturnal lifestyle is associated with the risk of several diseases such as metabolic syndrome and cancer. However, its role in sarcopenia remains unclear. The synergy of single-cell RNA sequencing and Mendelian randomization (MR) analysis provides an opportunity to reveal the important involvement of circadian rhythms in the pathogenesis of sarcopenia. Data quality control and normalisation were performed in the single-cell dataset, GSE167186. Then, different cell types were obtained by cell annotation through marker genes. Differentially expressed genes (DEGs) were further analyzed in different cell types. The intersection of DEGs and circadian-related genes in fast skeletal muscle cell were taken. Afterwards, the genes that had causal relationship with sarcopenia were selected as biomarkers by MR analysis. Variations in signaling pathways between different cell types were further analyzed. In GSE167186, 20 different cell populations identified by UMAP cluster analysis were further annotated to 8 cell types using maker genes. Afterwards, 44 DEGs were screened between fast skeletal muscle cell and circadian-related genes. Further MR Analysis yielded three genes with significant causal association with sarcopenia, which could be used as biomarkers in this study. SMARCD3 was found to have a protective effect against sarcopenia (OR = 0.9183, 95% CI = 0.8577-0.9832, p = 0.0144); in contrast, CPED1 (OR = 1.0292, 95% CI = 1.0089-1.0500, p = 0.0047) and FNBP4 (OR = 1.1096, 95% CI = 1.0316-1.1934, p = 0.0051) were associated with an increased risk of sarcopenia. The analysis of intercellular signaling revealed that the loss of the protective factor SMARCD3 in fast skeletal muscle cell triggers a specific upregulation of EGF signaling directed at FAPs. This study highlights the contribution of circadian rhythms in the pathogenesis of sarcopenia and further defines circadian rhythm-related biomarkers in sarcopenia, as demonstrated by MR analysis and scRNA-seq analysis. This suggests circadian rhythms as a focal point for pathogenesis research and potential therapeutic targeting in sarcopenia.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874402","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":"CPNE1 modulates Parkinson's disease risk through peripheral immune cell function: a cross-tissue and single-cell causal inference study.","authors":"Jing Zhao, Jia Fu, Jingjing Zhang, Zhongchi Zhang, Xue Bai, Lifen Yao","doi":"10.1007/s00335-026-10236-1","DOIUrl":"10.1007/s00335-026-10236-1","url":null,"abstract":"<p><p>It has been increasingly recognized that, to a significant extent, the peripheral immune system is playing a role in the etiology of Parkinson’s disease (PD). It has been reported recently that there may be multiple types of genetic susceptibility factors influencing the risk of PD through alterations in the functions of particular immune cells; at present, the precise mechanisms involved remain unclear. Based on a multi-dimensional causality inference model that included data from genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL) and single-cell eQTL (sc-eQTL), we performed both cross-tissue Mendelian randomization (MR) analysis and immune cell-specific MR analysis to investigate the association between genetic risk factors and peripheral immune functions based on individuals with PD. We found that the genetic prediction of CPNE1 expression had a negative association with PD risk in whole blood, substantia nigra and several immune cell types. The results support a possible protective relationship between CPNE1 and PD risk; however, the subsequent biological mechanism remains unclear. Genetically predicted CPNE1 expression showed a significant association with lower PD risk at the level of immune cells in nine different subtypes: T cells, monocytes, natural killer cells and so on. In addition, the exploratory immune-infiltration analysis of peripheral-blood transcriptomics data showed that there was a positive correlation of CPNE1 expression with the inferred number of regulatory T-cells; therefore, this result requires confirmation in subsequent studies. Our results suggest that CPNE1 could be a candidate factor for the reduced PD risk in blood, substantia nigra and several immune cell subsets. The above results suggest that peripheral immune regulation is likely associated with the link between CPNE1-relevant pathways and PD; however, it cannot determine the intermediate steps linking peripheral immune effects to neuroprotection in the brain.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874454","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":"Contrasting the genetic architecture of cardiac glutathione against other organs: unveiling a unique tissue-specific locus.","authors":"Jessica Strosahl, Susan McClatchy, Gary A Churchill, Rebecca L Koch, Steven W Craig, Robert Pazdro","doi":"10.1007/s00335-026-10222-7","DOIUrl":"10.1007/s00335-026-10222-7","url":null,"abstract":"<p><p>Glutathione is a ubiquitous antioxidant with critical roles in xenobiotic clearance and aerobic metabolism. Reduced glutathione (GSH) is converted to its oxidized counterpart, GSSG, in the process of neutralizing free radicals and maintaining biochemical homeostasis. An imbalance between free radical generation and antioxidant protection leads to oxidative stress and diminished GSH concentrations. Polymorphisms in GSH synthesis and metabolism genes have been associated with cardiovascular disease (CVD) development and progression, highlighting the critical need to explore the link between GSH system genetics and CVD. While those prior studies have focused on canonical GSH genes such as glutathione peroxidases (GPx), few studies to this date have investigated whether genes outside of traditional GSH pathways may be impacting the cardiac GSH redox system. Here, we performed high-precision genetic mapping using the Diversity Outbred (DO) mouse stock which revealed novel loci and genes underlying the cardiac GSH system. Mapping results indicated a locus on murine chromosome 14 at 54.240 Mbp associated with cardiac GSH concentrations, and bioinformatics analyses delineated five potential candidate genes: Slc7a7, Myh6, Myh7, MiR-208a, and Nfatc4. In addition, statistical analyses revealed notable variation in the cardiac GSH redox system under normal physiological conditions and correlations between cardiac and renal GSH phenotypes in the same cohort of mice. Overall, these findings expand our current knowledge of the vital GSH system, reveal novel genetic regulation of cardiac GSH status, and present candidate genes to be tested in future mechanistic studies.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13160963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874517","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":"Neurodevelopment as a shared genetic etiology linking sleep-related phenotypes and psychiatric disorders: a genome-wide pleiotropic analysis.","authors":"Yanmei Lin, Weimin Li, Xiaoxue Yang, Shuangyan Li, Jihong Liu, Lianhong Lin, Bin Zhang","doi":"10.1007/s00335-026-10232-5","DOIUrl":"10.1007/s00335-026-10232-5","url":null,"abstract":"<p><p>Comorbidity and mutual transformation between psychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorder, post-traumatic stress disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and anxiety disorders) and sleep disorders are common, with circadian rhythm disruption considered a potential biological basis, and neurodevelopmental abnormalities seemingly playing a key role. However, the extent to which shared genetic determinants contribute to these associations remains unclear. Extensive genetic correlations and overlaps were observed between sleep-related phenotypes and psychiatric disorders, with Mendelian randomization analysis further suggesting vertical pleiotropy in 21 of these pairs. Pleiotropic analysis identified 71,733 pleiotropic single nucleotide variants, 718 pleiotropic loci, and 226 co-located loci, with 1,225 candidate pleiotropic genes enriched in phenotypes related to neurodevelopment and brain tissues. A total of 187 candidate pleiotropic genes were screened through Polygenic Priority Score or summary data-based Mendelian Randomization. Pathway enrichment analysis further highlighted biological pathways primarily involving neurodevelopment, synaptic structure, and rhythmic behaviors. Additionally, key hub genes such as HNRNPK, GNL3 and YWHAE exhibited peak expression during early prenatal stages, followed by a decline or plateau throughout life. This study reveals a broad spectrum of pleiotropic genes shared between psychiatric disorders and sleep-related phenotypes, highlighting neurodevelopment as a key mechanism underlying their comorbidity. These findings provide new insights into potential therapeutic targets for these conditions.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874494","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":"FES eQTL suppresses the progression of primary aldosteronism by regulating CD3 on TD CD8br immune cells: Mendelian randomization and mediation analysis.","authors":"Cai Deng, Huasheng Liao, Yizhao Wu, Zijian Ao, Lichao Zhang","doi":"10.1007/s00335-026-10235-2","DOIUrl":"10.1007/s00335-026-10235-2","url":null,"abstract":"<p><p>The pathogenesis of primary aldosteronism (PA) remains incompletely understood. Current pharmacological therapies have significant limitations, thus highlighting the importance of recognizing new therapeutic targets for the diagnosis and treatment of PA. This study employed two-sample Mendelian randomization (MR) analysis, colocalization, summary data-based Mendelian randomization (SMR) analysis, and mediation analysis to recognize new therapeutic targets for the diagnosis and treatment of PA. Our analysis revealed a significant positive connection between increased FES eQTL expression and reduced PA risk. Concurrently, to elucidate the underlying metabolic mechanisms through which the FES eQTL influences PA, we identified immune cells as significant mediators of this pathway. Specifically, The FES eQTL was found to elevate the risk level of CD3 expression on TD CD8br immune cells (OR = 1.116885, 95% CI = 1.037747-1.202059, p = 3.20E-03), whereas elevated CD3 expression on TD CD8br immune cells reduced the risk of PA (OR = 0.6382, 95% CI = 0.428972-0.949479, p = 2.67E-02). On the basis of the aforementioned relationships, we ultimately determined that FES suppresses PA through a potential metabolic mechanism that involves immune cell modulation. We identified and verified the FES eQTL as a new cis-eQTL-mediated susceptibility gene that can reduce the risk of PA among druggable genes. Concurrently, we observed that the FES eQTL suppresses PA through a potential metabolic mechanism that involves the regulation of CD3 on TD CD8br immune cells, thereby providing a new therapeutic target for PA diagnosis and treatment.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874473","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":"Impact of scale parameter for marker variance prior in some Bayesian whole-genome regression methods.","authors":"Özge Kozakli, Ayhan Ceyhan","doi":"10.1007/s00335-026-10233-4","DOIUrl":"10.1007/s00335-026-10233-4","url":null,"abstract":"<p><p>In this study, traditional single-trait Bayesian whole-genome regression methods (BayesA, BayesB, and BayesCπ), which treat the scale parameter of the marker variance prior as fixed, were compared to alternative versions (BayesSA, BayesSB, and BayesSCπ) that estimate this parameter from the data using a Gamma prior. Analyses were conducted using a publicly available dataset of 3,534 animals from a commercial PIC pig population with genotypic and phenotypic records. Model performance for each trait was evaluated through six-fold cross-validation, using the correlation between genomic estimated breeding values (GEBV) and pseudo estimated breeding values (pEBV) as the measure of predictive accuracy. The alternative BayesSA model achieved higher accuracy than BayesA, whereas BayesSB showed no improvement, likely because its estimated scale parameters were similar to the fixed values in BayesB. For BayesCπ, results confirmed that the limited influence of the prior on marker variance led to similar performance between the classical and alternative versions. Heritability was estimated for five traits (T1–T5), and model specification affected these estimates slightly. The alternative models, which estimate prior variance parameters from the data rather than assuming them as fixed, generally produced lower heritability estimates than their classical counterparts. Considering that the reference heritability values from the original PIC study were based on extensive pedigree and high-density genotype data, the alternative models’ estimates can be regarded as reasonably consistent. These findings indicate that hyperparameter estimation in Bayesian models can improve prediction accuracy and the reliability of heritability estimates, providing a more suitable framework for traits with complex genetic architectures.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775554","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":"PI3KCD gene expression and its role in diabetic intervertebral disc degeneration running title: PI3KCD gene crucial for diabetic IDH.","authors":"Peng Wang, Feng Zhou","doi":"10.1007/s00335-026-10234-3","DOIUrl":"10.1007/s00335-026-10234-3","url":null,"abstract":"<p><p>Diabetes mellitus (DM) affects 8% of the population and impacts various connective tissues. Obesity, type 2 diabetes mellitus (T2DM), and their metabolic effects are increasingly linked to intervertebral disc degeneration (IVDD). Diabetic patients develop disc degeneration at younger ages and with higher frequency than non-diabetics. To investigate the role of PI3KCD in high glucose-induced IVDD and explore potential therapeutic approaches. The study examined PI3KCD expression in nucleus pulposus (NP) cells under high glucose conditions and investigated its regulatory mechanism through the PI3K/AKT pathway. The effects of PI3KCD agonist 740Y-P were also evaluated. High glucose conditions significantly decreased PI3KCD expression in NP cells. PI3KCD knockdown accelerated high glucose-induced NP cell death. The study revealed PI3KCD regulates NP cells via the PI3K/AKT pathway, with high glucose potentially reducing PI3KCD expression through increased cellular oxidative stress. The PI3KCD agonist 740Y-P demonstrated potential in partially reversing diabetes-induced IVDD, presenting a promising therapeutic approach for diabetic IVDD treatment.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775624","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}