Metabolism open最新文献

{"title":"Baseline metabolite profiles predict the glucose-lowering efficacy of exenatide in patients with type 2 diabetes","authors":"Yunyi Le ,&nbsp;Jin Yang ,&nbsp;Qi Wu ,&nbsp;Fei Li ,&nbsp;Wei Fu ,&nbsp;Wenhua Xiao ,&nbsp;Haining Wang ,&nbsp;Tianpei Hong ,&nbsp;Rui Wei","doi":"10.1016/j.metop.2026.100453","DOIUrl":"10.1016/j.metop.2026.100453","url":null,"abstract":"<div><h3>Aims</h3><div>Individual heterogeneity in the glucose-lowering response to glucagon-like peptide-1 receptor agonists (GLP-1RAs), including exenatide, limits efficient treatment selection for type 2 diabetes mellitus (T2DM). This study assessed whether baseline clinical characteristics together with serum metabolomic features could predict the glucose-lowering efficacy of exenatide.</div></div><div><h3>Methods</h3><div>A total of 93 Chinese adults with T2DM received exenatide treatment for 16 weeks. Treatment response was defined by glycated hemoglobin (HbA1c) change value (ΔHbA1c): responders (ΔHbA1c ≤ −0.3%, n = 70) and non-responders (ΔHbA1c &gt; −0.3%, n = 23). Baseline serum metabolites were profiled by non-targeted liquid chromatography–mass spectrometry. Predictors of exenatide-induced glucose-lowering response were screened and modeled using univariate and multivariate logistic regression analysis and evaluated with receiver-operating characteristic (ROC) analysis.</div></div><div><h3>Results</h3><div>At baseline, responders presented with a higher HbA1c level and a lower HDL-C level than non-responders. Logistic regression analysis indicated that baseline HbA1c and HDL-C levels were associated with ΔHbA1c after treatment. Metabolomic comparison analysis identified 15 discriminative serum metabolites between two groups. Among these metabolites, butenylcarnitine, LysoPC(18:2(9Z,12Z)) and PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z)) were correlated with the exenatide-induced glucose-lowering response. Baseline clinical characteristics (higher HbA1c level and lower HDL-C level) combined with the metabolomic features [lower butenylcarnitine, higher LysoPC(18:2(9Z,12Z)) and higher PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z)] predicted better glucose-lowering response to exenatide, with a sensitivity, specificity and area under the ROC curve of 78.1%, 90.0% and 0.895, respectively.</div></div><div><h3>Conclusions</h3><div>Combination of the baseline clinical characteristics (HbA1c and HDL-C) and metabolite profiles [butenylcarnitine, LysoPC(18:2(9Z,12Z)) and PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z))] can effectively predict glucose-lowering efficacy of exenatide in patients with T2DM.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"29 ","pages":"Article 100453"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380210","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":"First European case of Geller syndrome complicated with hypokalemic nephropathy: A case report and literature review","authors":"Efstratios Gavriilidis ,&nbsp;Christina Antoniadou ,&nbsp;Georgia Dimopoulou ,&nbsp;Evangelos Papadimitriou ,&nbsp;Stefania-Aspasia Bakola ,&nbsp;Charalampos Papagoras ,&nbsp;Panagiotis Skendros ,&nbsp;Dimitrios Tsilingiris","doi":"10.1016/j.metop.2025.100429","DOIUrl":"10.1016/j.metop.2025.100429","url":null,"abstract":"<div><div>Geller syndrome is caused by a gain-of-function mutation in the mineralocorticoid receptor (MR), rendering it prone to activation by elevated progesterone levels during pregnancy. It is characterized by gestational hypertension and hypokalemia. We describe the case of a 35-year-old primigravida, who presented at 22 weeks of gestation with severe hypokalemia and hypertension, complicated by hypokalemic nephropathy manifesting as diabetes insipidus and proteinuria. Initial potassium replacement, eplerenone administration and desmopressin were insufficient, whereas the administration of amiloride, a potassium-sparing diuretic that inhibits epithelial sodium channels (ENaC) in the distal nephron, led to complete resolution of the clinical syndrome. The patient had no further complications and delivered a healthy infant at 37 weeks. Genetic testing did not reveal known MR mutations, suggesting that other genetic variants or epigenetic changes in MR may warrant future investigation, particularly in isolated populations. To date, 17 cases of Geller syndrome have been reported in the literature including the herein presented, which is to the best of our knowledge the first documented in Europe. Genetic testing was performed in only one case, apart from the initially reported ones. Urgent delivery was required in four cases, while amiloride, the treatment of choice, was administered in only five, highlighting the importance of early recognition of the syndrome for effective management and prevention of adverse pregnancy outcomes.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"29 ","pages":"Article 100429"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145739276","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":"Interactions between serum uric acid and gut microbiota: implications for metabolic health","authors":"Nurshad Ali","doi":"10.1016/j.metop.2025.100438","DOIUrl":"10.1016/j.metop.2025.100438","url":null,"abstract":"<div><div>Serum uric acid (SUA), the end product of purine metabolism, is a known risk factor for developing gout; however, recent evidence suggests its broader role in metabolic disorders. The gut microbiota, a complex microbial ecosystem, plays a crucial role in influencing purine metabolism and intestinal uric acid (UA) excretion. Recent findings have uncovered a two-way relationship: certain microbes can metabolize purines and UA, while elevated UA can reduce microbial diversity, alter the production of SCFAs, and compromise intestinal barrier function. These interactions are linked to obesity, insulin resistance, T2D, NAFLD, and CVD, connecting purine metabolism with overall metabolic health. This review synthesizes current experimental and clinical evidence on SUA-microbiota interactions, with an emphasis on microbial enzymes, host urate transporters, and microbial metabolites, including bile acids and SCFAs. It also discusses therapeutic implications, spanning urate-lowering drugs to microbiota-targeted strategies, including probiotics, prebiotics, and dietary modulation. Despite progress, significant gaps remain: most human studies are cross-sectional, microbial taxa influencing SUA remain inconsistent, and interindividual microbiome variability limits the translation of findings to personalized care. Future multi-omics and longitudinal approaches are necessary to elucidate causal pathways and identify biomarkers, ultimately informing innovative strategies for the prevention and treatment of metabolic diseases beyond gout.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"29 ","pages":"Article 100438"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926228","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":"Obesity-induced cognitive impairment: Underlying mechanisms and therapeutic prospects","authors":"Kai Liu ,&nbsp;Shu Liu ,&nbsp;Dong Wang ,&nbsp;Hong Qiao","doi":"10.1016/j.metop.2026.100444","DOIUrl":"10.1016/j.metop.2026.100444","url":null,"abstract":"<div><div>The prevalence of obesity continues to rise worldwide. Obesity is not only a core risk factor for chronic metabolic diseases, but also significantly associated with the risk of cognitive impairment. Obesity in middle age can cause aprosexia, cognitive disorder, dementia, hypomnesis, and increase the risk of execution decline, depression and anxiety. The underlying mechanisms involve multiple pathological pathways such as neuroinflammation, imbalance of gut microbiota-gut-brain axis, metabolic abnormalities, and imbalance of adipokines. Obesity induced chronic inflammation impairs neuroprotection by activating microglia, exacerbating β-amyloid deposition and neurodegeneration. Intestinal flora disorder impairs neuroprotection by reducing the production of short-chain fatty acids. Metabolic syndrome has synergistic damage to cerebral vascular and white matter microstructure. Genetic factors, comorbidities and ethnic differences clearly moderated the association between obesity and cognition. Among the interventions, bariatric surgery can improve executive function and memory, while lifestyle modification and drug intervention have protective effects by reducing inflammation and metabolic disorders. In the future, we need to focus on precise intervention strategies, such as developing multi-dimensional biomarkers, and optimizing obesity assessment indicators to overcome the limitations of existing studies, so as to provide a basis for phased and individualized prevention and treatment.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"29 ","pages":"Article 100444"},"PeriodicalIF":2.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023110","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 role of AMPK signaling pathway in the pathogenesis of type 2 diabetes mellitus with its complications and related metabolic disorders","authors":"Kibur Hunie Tesfa ,&nbsp;Chernet Desalegn Gebeyehu ,&nbsp;Asrat Tadele Ewunetie ,&nbsp;Endalkachew Gugsa ,&nbsp;Amare Nigatu Zewdie ,&nbsp;Gashaw Dessie ,&nbsp;Hiwot Tezera Endale","doi":"10.1016/j.metop.2025.100397","DOIUrl":"10.1016/j.metop.2025.100397","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) is the most common group of metabolic disorders in the world, characterized by hyperglycemia that leads to severe short-term complications such as ketoacidosis, hyperosmolar hyperglycemic coma, and long-term microvascular complications that affect the eye, kidney, and nerves. Type 2 diabetes occurs due to resistance to insulin. AMPK (adenosine monophosphate-activated protein kinase) is an energy radar that controls various metabolic and physiological processes. It is dysregulated in major chronic diseases, such as diabetes. The focus of this review is on understanding the role of AMPK in type 2 diabetes mellitus, which helps ameliorate hyperglycemia and its complications. Medications for T2DM are designed to upregulate the AMPK signaling pathway to improve its microvascular and macrovascular complications. AMPK signaling interacts with PGC-1, PI3K/Akt, NOX4, NF-κB, and other molecular pathways to produce such protective effects. Thus, AMPK is emerging as one of the most auspicious targets for both the prevention and treatment of type 2 diabetes mellitus. Hence, this review focuses on the recent evidence of the role of AMPK signaling in type 2 diabetes mellitus pathogenesis and how to circumvent its complications.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100397"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145121233","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":"Maternal and cord blood lipidomics as predictors of autism spectrum disorders: A systematic review","authors":"Antigoni Sarantaki ,&nbsp;Ali Ghanchi ,&nbsp;Joeri Vermeulen ,&nbsp;Anastasia Barbouni ,&nbsp;Ekaterina Charvalos ,&nbsp;Aikaterini Sousamli ,&nbsp;Dimitrios K. Anagnostopoulos","doi":"10.1016/j.metop.2025.100403","DOIUrl":"10.1016/j.metop.2025.100403","url":null,"abstract":"<div><h3>Background</h3><div>Lipid metabolism is integral to neurodevelopment, contributing to neuronal membrane integrity, myelination, and signaling processes. Recent evidence indicates that disruptions in maternal and perinatal lipidomic profiles may be linked to an increased risk of autism spectrum disorders (ASD). To date, no systematic review has synthesized findings from human cohort studies examining lipidomic biomarkers during pregnancy or at birth in relation to subsequent ASD development.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed/MEDLINE, Embase, Scopus, Web of Science, Google Scholar, PsycINFO, CINAHL, and grey literature sources from inception to September 2025 for studies assessing maternal lipidomics during pregnancy, postpartum lipid profiles, or cord/neonatal lipidomics in relation to ASD diagnoses or autistic traits measured in offspring. Eligible study designs included prospective cohorts and nested case–control studies. Data extraction followed a standardized template, and methodological quality was appraised using the Newcastle–Ottawa Scale (NOS). Findings were synthesized narratively given heterogeneity in biospecimen timing, lipidomic platforms, and outcome measures. The protocol was registered with PROSPERO (CRD420251152074).</div></div><div><h3>Results</h3><div>Nine prospective studies met the inclusion criteria. Maternal lipidomics during pregnancy indicated that lower ω-3 to ω-6 polyunsaturated fatty acid ratios and deficiencies in docosahexaenoic acid were associated with increased autistic traits or ASD with intellectual disability. Postpartum maternal lipid profiles showed that low low-density lipoprotein (LDL) cholesterol predicted greater ASD risk. Cord blood and neonatal lipidomics implicated acylcarnitines, sphingomyelins, and arachidonic acid–derived oxylipins in later ASD symptoms, with some studies demonstrating moderate predictive accuracy (AUROC ranging from 0.71 to 0.85) using machine learning approaches. Overall, recurrent disturbances in fatty acid metabolism, mitochondrial β-oxidation, and inflammatory lipid mediators were observed.</div></div><div><h3>Conclusions</h3><div>Prospective evidence supports an association between maternal and neonatal lipidomic alterations and ASD risk, suggesting potential early biomarkers. However, heterogeneity across studies and reliance on single-timepoint measures limit comparability. Standardized lipidomic protocols, longitudinal sampling, and replication in diverse cohorts are needed to establish clinical utility and inform prevention strategies.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100403"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268133","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":"Cross-sectional mediation analysis of systemic inflammation in the association between serum uric acid and diabetic kidney disease: Evidence from NHANES 1999–2018","authors":"Jiaying Wang ,&nbsp;Weijing Liu ,&nbsp;Jiaoyan Li ,&nbsp;Mengxiao Li ,&nbsp;Heyan Feng ,&nbsp;Shangfei Liu ,&nbsp;Yanzhe Cheng ,&nbsp;Wei Li","doi":"10.1016/j.metop.2025.100426","DOIUrl":"10.1016/j.metop.2025.100426","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate whether systemic inflammation, quantified by the Aggregate Index of Systemic Inflammation (AISI), mediates the association between uric acid (UA) and diabetic kidney disease (DKD).</div></div><div><h3>Study design</h3><div>We analyzed data from 1716 adults with diabetes in NHANES 1999–2018. We used regression to assess UA-AISI-DKD associations and mediation analysis to quantify AISI's indirect effect. A random forest model, interpreted via SHAP, predicted DKD risk.</div></div><div><h3>Results</h3><div>Each 1 mg/dL increase in UA was associated with a 14 % higher DKD risk (adjusted OR = 1.14, 95 % CI: 1.04–1.26). UA was positively associated with AISI (β = 0.0356, p = 0.0058), which in turn predicted DKD (OR = 1.25 per SD increase in ln-AISI, 95 % CI: 1.10–1.42). AISI partially mediates (10.94 %) the association between UA and DKD, indicating that systemic inflammation is one of several pathways linking hyperuricemia to renal injury. The random forest model performed best, with SHAP highlighting AISI as a key positive predictor.</div></div><div><h3>Conclusion</h3><div>Systemic inflammation, as measured by AISI, partially mediates the cross-sectional association between serum uric acid and diabetic kidney disease, supporting inflammation as one of several contributing pathways. The predictive performance of models incorporating AISI remains modest and does not outperform conventional clinical risk scores.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100426"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684481","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":"Update on the impact of lipid and glucose control on diabetic wound healing","authors":"Rui Sun,&nbsp;Yang Xu,&nbsp;Zhenjun Ji,&nbsp;Xingxing Li,&nbsp;Zaixiao Tao,&nbsp;Weichen Luo,&nbsp;Yuyu Yao,&nbsp;Lijuan Chen,&nbsp;Genshan Ma","doi":"10.1016/j.metop.2025.100408","DOIUrl":"10.1016/j.metop.2025.100408","url":null,"abstract":"<div><div>This review summarizes current insights into the molecular mechanisms by which hyperglycemia and dyslipidemia contribute to chronic diabetic wounds. It discusses the roles of key metabolic pathways, including the hexosamine biosynthetic and polyol pathways, along with the significance of inflammatory mediators and oxidative stress in this process. In addition, emerging therapeutic strategies are evaluated, such as the use of metformin to activate AMPK, PPAR agonists, SGLT2 inhibitors, and GLP-1 receptor agonists, which hold promise for modulating the inflammatory microenvironment and restoring cellular function. Combination therapies, advanced wound dressings, negative pressure wound therapy (NPWT), hyperbaric oxygen therapy (HBOT), and regenerative approaches such as stem cell therapies and bioengineered skin substitutes are also reviewed as integrated strategies that target both systemic metabolic dysregulation and local wound-specific challenges. These findings underscore the critical role of improved glucose and lipid control in optimizing diabetic wound healing and suggest that personalized, multimodal therapeutic approaches may offer enhanced clinical outcomes for patients with diabetic ulcers and other chronic wounds.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100408"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519830","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":"Association of sleep quality and glycemic variability among South Indian rural patients with Type-2 diabetes mellitus","authors":"Mohammed Azhar Hussain ,&nbsp;H. Anil Kumar ,&nbsp;Mahadevamma Lingaiah","doi":"10.1016/j.metop.2025.100427","DOIUrl":"10.1016/j.metop.2025.100427","url":null,"abstract":"<div><h3>Background</h3><div>Sleep quality plays a vital role in glucose homeostasis and may influence glycemic variability among diabetic individuals. The main objective of this study is to investigate the relationship between subjective sleep quality and glycemic variability in patients with Type-2 diabetes mellitus (T2DM).</div></div><div><h3>Methods</h3><div>Sixty-two adults with type 2 diabetes mellitus underwent Continuous Glucose Monitoring (CGM) and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Patients with at least three days of valid CGM data were included in the analyses. Glycemic variability was quantified using coefficient of variation (%CV). Spearman's correlation and multiple linear regression modelling were used to examine the association between glycemic variability (%CV) and sleep quality.</div></div><div><h3>Results</h3><div>Sleep-efficiency showed a significant positive correlation with %CV (r = 0.28, p = 0.03), whereas greater sleep disturbances were associated with lower TBR (r = −0.27, p = 0.04). A %CV threshold of 32.3 was identified as a cutoff for distinguishing stable and unstable glycemic patterns; however, this threshold is exploratory and requires further validation. In multiple linear regression analyses reduced sleep efficiency (β = 7.77, p = 0.002) was significantly associated with higher glycemic variability, while sleep medication use (β = −2.12, p = 0.01) also showed significant association after adjustment for HbA1c, microvascular and macrovascular complications.</div></div><div><h3>Conclusion</h3><div>Poor sleep quality, particularly sleep efficiency exhibited a significant relationship with glycemic variability. Improving sleep quality may represent a practical and modifiable strategy to improve glycemic stability in this population.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100427"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684482","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":"Novel causal associations between plasma metabolites and prostate cancer risk revealed by mendelian randomization","authors":"Hanghang Chen ,&nbsp;Huiduo Zhao ,&nbsp;Bingxin Meng ,&nbsp;Qi Liu","doi":"10.1016/j.metop.2025.100421","DOIUrl":"10.1016/j.metop.2025.100421","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is a major global health concern for men, yet its underlying metabolic mechanisms are not fully understood. Identifying causal metabolites could reveal novel pathways for risk assessment and prevention.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive two-sample Mendelian randomization (TSMR) study following STROBE-MR guidelines. Genetic instruments for plasma metabolites were derived from two independent sources, including the METSIM study, a cohort exclusively comprising Finnish men, and the Canadian Longitudinal Study on Aging (CLSA). Summary-level data for PCa were obtained from the PRACTICAL consortium and FinnGen. Inverse variance weighted (IVW) was the primary analysis method, supplemented by sensitivity analyses and Bayesian colocalization (coloc) to assess shared causal genetic variants, a key methodological strength enhancing causal inference.</div></div><div><h3>Results</h3><div>Our analysis identified four plasma metabolites with a significant causal relationship with PCa risk. Ribitol was associated with a reduced risk, while N2,N5-diacetylornithine, N-acetylarginine, and N-acetylcitrulline were associated with an elevated risk. These findings were consistent across datasets and robust in sensitivity analyses. Colocalization analysis provided strong evidence (PP.H4 &gt; 0.8) for a shared causal variant at the rs10201159 locus between N2,N5-diacetylornithine and PCa.</div></div><div><h3>Conclusion</h3><div>This study provides robust genetic evidence supporting a causal role of specific plasma metabolites in prostate cancer development. The incorporation of a male-exclusive metabolomic dataset (METSIM) strengthens the validity of our findings for this male-specific cancer. These metabolites represent promising candidates for further mechanistic investigation into prostate cancer etiology and potential translation into clinical biomarkers.</div></div>","PeriodicalId":94141,"journal":{"name":"Metabolism open","volume":"28 ","pages":"Article 100421"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519827","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}