Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.","authors":"Acily Skadon Worral Wilfred Raj, Jaithanya Yesupogu Moorthy Babu, Rajalakshmi Sabanayagam, Sridhar Muthusami, Ravi Manoharan","doi":"10.1007/s00109-026-02730-5","DOIUrl":"https://doi.org/10.1007/s00109-026-02730-5","url":null,"abstract":"<p><p>Colorectal cancer (CRC) cells undergo significant alterations in glucose and glutamine metabolism to support rapid growth and migration. However, the molecular mechanisms underlying these metabolic changes remain incompletely understood. Although NUAK1 and NUAK2, members of the NUAK kinase family have been implicated in CRC tumorigenesis, their specific roles in metabolic reprogramming that drives CRC progression and metastasis have not been elucidated. In this study, we demonstrate that NUAK1 and NUAK2 are overexpressed in human CRC tissues and that their expression is associated with increased tumor metastasis and poorer patient survival. NUAK1/2 promotes CRC cell proliferation and migration, whereas their depletion markedly reduces cell growth and migratory capacity. Furthermore, knockout of NUAK1/2 disrupts key metabolic pathways, including aerobic glycolysis, pentose phosphate pathway (PPP), and glutamine metabolism. Mechanistically, NUAK1/2 facilitates mTOR-driven metabolic reprogramming and promotes CRC growth and migration by suppressing AMPK activity. Depletion of NUAK1/2 impairs metabolic function, cellular growth, and migration potential in CRC cells, effects that are further enhanced by pharmacological activation of AMPK with AICAR and inhibition of mTOR using Rapamycin. In conclusion, these findings identify NUAK1/2 as critical regulators of CRC progression and migration through AMPK/mTOR-mediated metabolic reprogramming, highlighting their potential as therapeutic targets in colorectal cancer.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention.","authors":"Liqi Liao, Zhe Zhai, Linglin Zhong, Chenyu Shi, Shunyu Yao, Lingling Tao, Yong-Xian Cheng, Xuhan Liu","doi":"10.1007/s00109-026-02729-y","DOIUrl":"https://doi.org/10.1007/s00109-026-02729-y","url":null,"abstract":"<p><p>As early as 1931, bacillus Calmette-Guérin (BCG) vaccination was hypothesized to reduce neonatal mortality through nonspecific immune stimulation. The concept of trained immunity was formally proposed in the 21st century, and clinical observations during the COVID-19 pandemic further stimulated interest in the possibility that BCG vaccination might confer broad, non-specific protection against heterologous infections. Trained immunity represents a paradigm-shifting concept in immunology, defining the innate immune system's ability to develop a memory-like state through persistent epigenetic and metabolic reprogramming following initial stimulus exposure. This process enables enhanced, nonspecific responses upon re-exposure, extending immune memory beyond adaptive immunity. The dual role of trained immunity is context-dependent: it is protective in acute infections by improving pathogen clearance, but pathogenic in chronic conditions such as atherosclerosis and certain tumor microenvironments, where sustained proinflammatory memory promotes disease progression. Central mechanisms involve mTOR-HIF-1α signaling, metabolic rewiring of mevalonate/cholesterol pathways, and histone modifications including H3K4me3 and H3K27ac. This review systematically synthesizes the cellular basis, inducing factors, and disease spectrum of trained immunity, providing a conceptual framework for advancing host-directed therapies and precision immunology in infectious, inflammatory, and oncological contexts.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper-induced suppression of the PPARα-FABP1 axis sensitizes hepatocytes to ferroptosis in Wilson disease.","authors":"Yingjie Li, Yaoyi Wu, Yanwen Zhou, Liyan Zhao, Zhenyu Xu, Yimin Zhang, Ning Zhou","doi":"10.1007/s00109-026-02725-2","DOIUrl":"10.1007/s00109-026-02725-2","url":null,"abstract":"<p><p>Wilson disease (WD) is characterized by hepatic copper accumulation and progressive liver injury, yet the mechanisms linking copper overload to hepatocellular damage remain incompletely understood. Here, we identify suppression of the PPARα-FABP1 axis as a key metabolic vulnerability that sensitizes hepatocytes to ferroptosis in WD. Liver tissues from WD patients and Atp7b^⁻/⁻ mice exhibited impaired antioxidant capacity, enhanced lipid peroxidation, and coordinated downregulation of PPARα-FABP1 signaling at both transcriptomic and proteomic levels. In hepatocytes, copper exposure increased nuclear-enriched copper and caused a time-dependent repression of PPARα and FABP1, lowered the threshold for RSL3-induced ferroptotic cell death, and enhanced lipid peroxidation. These effects were mimicked by silencing either PPARα or FABP1 and were partially rescued by ferroptosis inhibition. Integration of published lipidomic datasets revealed accumulation of peroxidized polyunsaturated fatty acids in WD, while FABP1 overexpression mitigated arachidonic acid-driven lipid peroxidation and ferroptosis. Clinically, hepatic expression and circulating levels of FABP1 declined with disease severity and were associated with inflammatory activity and fibrosis stage in WD patients, showing moderate predictive value for adverse outcomes. Together, these findings establish copper-induced suppression of the PPARα-FABP1 axis as a mechanistic link between metabolic dysregulation and ferroptosis in WD, highlighting a potential therapeutic vulnerability in copper-associated liver disease.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149140282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.","authors":"Hyungkuen Kim, Eunmi Hwang, Sung-Jo Kim","doi":"10.1007/s00109-026-02726-1","DOIUrl":"10.1007/s00109-026-02726-1","url":null,"abstract":"<p><p>Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human epididymis protein 4 is a predictor of long-term mortality and major adverse cardiovascular events in patients with coronary artery disease.","authors":"Axel Muendlein, Christine Heinzle, Kathrin Geiger, Eva Maria Brandtner, Laura Schnetzer, Angelika Hammerer-Lercher, Christoph H Saely, Heinz Drexel, Andreas Leiherer","doi":"10.1007/s00109-026-02727-0","DOIUrl":"10.1007/s00109-026-02727-0","url":null,"abstract":"<p><p>Human epididymis protein 4 (HE4; WFDC2) has emerged as a profibrotic biomarker associated with adverse outcomes across multiple diseases. However, its prognostic value in patients with established coronary artery disease (CAD) remains insufficiently characterized and was addressed in the present study. We prospectively studied 395 patients with angiographically confirmed CAD. Circulating HE4 levels were measured at baseline and analyzed both as log2-transformed values and by using a data-derived cut-off of 8.0 ng/mL, derived from Youden's index. The primary endpoints were major adverse cardiovascular events (MACE) and all-cause mortality during a 10-year follow-up. Multivariable Cox regression models were adjusted for traditional risk factors, including age, body mass index, hypertension, type 2 diabetes mellitus, LDL cholesterol, HDL cholesterol, and the presence of significant coronary artery disease (Model 1), and additionally for renal function, C-reactive protein, fibrinogen, and N-terminal pro-B-type natriuretic peptide (Model 2). Higher HE4 levels, analyzed as a log2-transformed continuous variable, indicated a significantly increased risk of MACE and all-cause mortality across all adjustment models, with HRs of 1.2-1.4 per doubling of HE4. Also, the categorical HE4 cut-off was significantly associated with all endpoints across all adjustment levels, and the addition of HE4 to the fully adjusted baseline model improved overall risk reclassification across all endpoints. In conclusion, HE4 is significantly associated with long-term cardiovascular outcomes and all-cause mortality in patients with established CAD and may provide prognostic information beyond inflammatory and cardiorenal markers.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular smooth muscle-specific NLRP3 hyperactivation exacerbates arterial intimal hyperplasia in mice.","authors":"Yun-Ting Wang, Alexandra K Moura, Rui Zuo, Wei Gao, Bradley K McConnell, Guangbi Li, Pin-Lan Li, Xiang Li, Yang Zhang","doi":"10.1007/s00109-026-02724-3","DOIUrl":"10.1007/s00109-026-02724-3","url":null,"abstract":"<p><p>Intimal hyperplasia is a major contributor to restenosis after vascular interventions and to atherosclerotic lesion progression, involving vascular smooth muscle cell (VSMC) inflammatory activation, phenotypic switching, and maladaptive remodeling. Although NOD-like receptor pyrin domain 3 (NLRP3)-associated inflammatory signaling has been linked to vascular diseases, in vivo evidence defining how VSMC-intrinsic NLRP3 hyperactivation contributes to VSMC dysfunction and intimal hyperplasia remains limited. Here, we generated a VSMC-specific Nlrp3 gain-of-function (GOF) knock-in (KI) mouse model (Nlrp3 ^{L351P/+/Myh11-Cre}, \"Nlrp3^SMKI\") and subjected it to carotid partial ligation under hypercholesterolemic conditions. VSMC Nlrp3 GOF was associated with increased caspase1 activation-associated signaling in vivo, including in unligated arteries, and further enhanced ligation-triggered caspase1 activation. Nlrp3^SMKI arteries exhibited heightened vascular inflammation, including VCAM1 upregulation and increased macrophage-associated accumulation, together with enhanced Gasdermin D (GSDMD)/GSDMD N-terminal-associated signaling and increased TUNEL-positive cell death. These changes were accompanied by significantly exacerbated neointimal lesion growth, as reflected by increased intimal area and intima-to-media ratio. VSMC Nlrp3 GOF was also associated with enhanced vascular injury-induced lipid accumulation and foam cell-like remodeling in the injured arterial wall, including α-SMA-positive VSMC-containing regions. These pathological responses were accompanied by reduced expression of the transcription factor EB (TFEB) and altered expression of lysosome-autophagy-related markers, suggesting an association between VSMC NLRP3 hyperactivation and disrupted cellular stress-adaptive pathways during vascular remodeling. Collectively, these data provide in vivo evidence that VSMC-specific Nlrp3 GOF exacerbates vascular injury-induced intimal hyperplasia and is accompanied by heightened vascular inflammation, GSDMD-associated cell injury signaling, lipid accumulation, foam cell-like remodeling, reduced TFEB expression, and altered lysosome-autophagy-related marker expression. These findings suggest that targeting VSMC NLRP3-associated inflammatory signaling may represent a potential therapeutic strategy for limiting restenosis and plaque progression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149122597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of follicular helper T cell subset differentiation in health and disease.","authors":"Qing Xin, Longhao Zhao, Jinghe Zhang, Xinyi Liu, Guangwei Liu","doi":"10.1007/s00109-026-02721-6","DOIUrl":"10.1007/s00109-026-02721-6","url":null,"abstract":"<p><p>Follicular helper T (T_FH) cells play a crucial role in adaptive humoral immunity. They provide help to B cells in the germinal centers (GCs), driving the affinity maturation of antigen-specific antibodies and class switch recombination. T_FH cells possess profound heterogeneity in spatial distribution (e.g., GC-T_FH, follicular mantle-T_FH, circulating T_FH, peripheral T_FH) and phenotypic characteristics (e.g., T_FH1, T_FH2, T_FH17), which enable T_FH cells to respond to diverse immune challenges. This review summarizes the recent progress, including our data, on the T_FH regulatory network driven by B-cell lymphoma 6 (Bcl-6) and cellular musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf), and the contradictory roles exhibited by different T_FH subsets under disparate pathological conditions such as viral infections, autoimmune diseases, and cancer. Integrating multiple T_FH subsets into a systematic framework can provide a new perspective for understanding humoral immune regulation and developing new targeted therapies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149077092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTCF-FXN regulatory axis plays critical roles in clinical assessments and disease progression of primary open-angle glaucoma.","authors":"Danrui Cai, Yao Yu, Junze Ma, Ting Li, Ziyao Liu","doi":"10.1007/s00109-026-02717-2","DOIUrl":"10.1007/s00109-026-02717-2","url":null,"abstract":"<p><p>Primary open-angle glaucoma (POAG) is an irreversible ophthalmic disease that is the leading cause of blindness. Oxidative stress (OS) is considered an important contributor to POAG pathogenesis. However, its mechanism of action in POAG remains vague. FXN was identified as a candidate OS-related gene associated with POAG through WGCNA and two machine learning methods (LASSO regression and SVM-RFE). Through multiple bioinformatic analyses, FXN exhibited potential diagnostic value and was associated with immune-related signatures in POAG samples. GSEA revealed that high FXN expression was associated with enrichment of glycolysis- and pyruvate metabolism-related gene sets. FXN expression was significantly decreased in an H2O2 in vitro model (R28 cells). CCK8, EdU, TUNEL, ROS detection and flow cytometry assays indicated that FXN overexpression improved retinal ganglion cells (RGCs) viability and inhibited cell apoptosis and ROS accumulation. Mechanistically, CTCF was demonstrated to transcriptionally regulate FXN by binding to its promoter region, as confirmed by ChIP assay. FXN deletion partially abolished the protective effects of CTCF overexpression on RGC viability, apoptosis, and oxidative stress responses. In conclusions, FXN may represent a potential biomarker associated with POAG. The identification of the CTCF-FXN regulatory axis provides new insights into the molecular mechanisms underlying POAG.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076900","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 orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells.","authors":"Matthias Weider, Magdalena C Wagner, Theresa Schmid, Sebastian Gehlen-Breitbach, Gabriele Rodrian, Nicolai Peschel, Holm Schneider, Kerstin U Ludwig, Michael Wegner, Lina Gölz","doi":"10.1007/s00109-026-02720-7","DOIUrl":"10.1007/s00109-026-02720-7","url":null,"abstract":"<p><p>Orofacial clefts represent the most prevalent congenital anomalies affecting the craniofacial region. They can be evoked by a disturbed development of either oral epithelium or cranial neural crest-derived mesenchyme, or by disruptions of their interplay. IRF6 is a well-known risk gene associated with non-syndromic orofacial clefts and causative for Van der Woude syndrome, an autosomal dominant syndrome characterized by orofacial clefting and lower lip pits. Its expression in the oral epithelium depends on the transcription factor TFAP2A. We here show by immunofluorescence on mouse embryonic sections and by mining of single cell RNA-seq data that IRF6 is also expressed in cranial neural crest-derived tissue in mice and humans, together with TFAP2A and SOX9. The IRF6 enhancer MCS-9.7 is bound and activated by the transcription factor SOX9, mutations of which cause Pierre Robin sequence, a craniofacial anomaly that includes cleft palate. This SOX9-dependent activation is influenced by the single nucleotide variant rs76145088 that is associated with orofacial clefting. Inactivation of Sox9 in a murine cranial neural crest cell line by CRISPR/Cas9 results in loss of Irf6 expression. We conclude that dysregulation of the SOX9-IRF6 axis in cranial neural crest cells could be relevant for the pathogenesis of orofacial clefting. KEY MESSAGES: Irf6 is co-expressed with Sox9 - the major gene mutated in Pierre Robin Sequence (a craniofacial anomaly that includes cleft palate) - in a subset of cranial neural crest cells. The IRF6 enhancer MCS-9.7 is bound and activated by SOX9 and different alleles of the orofacial cleft risk SNV rs76145088 in MCS-9.7 confer differential activation of this enhancer by SOX9. Inactivation of Sox9 via CRISPR/Cas9 in a cranial neural crest cell line prevents Irf6 expression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149066970","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":"Unravelling deregulated metabolites in seminal plasma of infertile men: a systematic review and bioinformatic analysis.","authors":"Rafael Santos, Beatriz Marinheiro, Margarida Ramos, Pedro F Oliveira, Pedro O Corda, Margarida Fardilha, Joana Santiago","doi":"10.1007/s00109-026-02719-0","DOIUrl":"10.1007/s00109-026-02719-0","url":null,"abstract":"<p><p>Male infertility is a multifactorial condition accounting for  50% of infertility cases. Although conventional semen analysis remains the standard method for male infertility diagnosis, it fails to explain 30% of the cases and their underlying molecular causes. Metabolomics offers valuable insights into sperm metabolic dysfunction, enabling the identification of deregulated pathways involved in male infertility. Here, a systematic review including metabolomic studies that compare the seminal plasma metabolome of healthy and infertile men was conducted. A literature search was conducted in PubMed, Scopus, and Web of Science databases following PRISMA guidelines. Twenty metabolomic studies published until December 2025 were included and categorized into four groups: asthenozoospermia, oligozoospermia, obesity, and overall male infertility. A total of 284 metabolites were retrieved, of which eleven (down: L-tyrosine, D-fructose, L-valine, phenylalanine, proline, D-glucose, L-alanine, leucine, sorbitol, L-aspartic acid; up: uridine), six (down: D-fructose, glycine, maleic acid, L-valine, proline, and lysine), and ten (down: L-carnitine, L-tyrosine, L-valine, L-alanine, phenylalanine, proline, D-glucose, leucine, malic acid, and citraconic acid) were altered in asthenozoospermia, obesity, and overall infertility groups, respectively. These metabolites were associated with phenylalanine/tyrosine metabolism, fructose and mannose degradation, and β-oxidation of long-chain fatty acids. A bioinformatic analysis of the enzymes possibly involved in these pathways revealed associations with male infertility phenotypes and key sperm functions, including motility, vitality, and energy metabolism. This study provides a list of metabolites altered in the seminal fluid of infertile men, highlighting their potential as biomarkers of male infertility, and gives insights into the metabolic pathways affected in these conditions.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149066975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}