{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:35:04Z","timestamp":1762320904261,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32271214"],"award-info":[{"award-number":["32271214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100017594","name":"Medical Science and Technology Project of Zhejiang Province","doi-asserted-by":"crossref","award":["2025KY002"],"award-info":[{"award-number":["2025KY002"]}],"id":[{"id":"10.13039\/501100017594","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Leukemia comprises heterogeneous hematologic malignancies, and whether circulating metabolites contribute causally to subtype-specific risk remains uncertain. Objectives: The aim of this study was to assess the causal effects of plasma metabolites for acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Methods: A two-sample Mendelian randomization (MR) using summary-level genome-wide association study statistics was conducted. For each metabolite, a single variant showing the strongest association with the metabolite that had the largest variance explained (R2) among the independent genome-wide significant (p &lt; 5 \u00d7 10\u22128) SNPs assigned to effector genes was selected as sentinel. Multiple comparisons using Bonferroni correction (0.05\/83 = 6.02 \u00d7 10\u22124) were applied to minimize the risk of obtaining false positive results. Results: Totally, 83 metabolites and metabolite ratios were analyzed for AML, CML, ALL, and CLL. Lithocholate sulfate (1), instrumented by the rs10425975 variant in the SULT2A1 gene, was significantly associated with an increased risk of CLL (OR = 2.19; 95% CI: 1.45\u20133.31; p = 2 \u00d7 10\u22124). An additional 17 metabolite-leukemia associations showed suggestive evidence of significance. Approximately 300 drug entries linked to candidate metabolites were curated to provide a basis for mechanistic follow-up. Conclusions: Our MR result supports a causal link between higher genetically proxied lithocholate sulfate (1) and increased CLL risk. The discovery of these \u201cmetabolite-gene-drug\u201d relationships suggests a central role in leukemia pathogenesis and warrants further functional investigation for their therapeutic potential.<\/jats:p>","DOI":"10.3390\/metabo15110719","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T18:21:46Z","timestamp":1762194106000},"page":"719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal Effects of Plasma Metabolites on Leukemia: A Mendelian Randomization Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6300","authenticated-orcid":false,"given":"Chang","family":"Huang","sequence":"first","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5426-0217","authenticated-orcid":false,"given":"Yuchen","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health, Institute of Nutrition and Food Safety, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengjie","family":"Li","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Ye","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nannan","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Meng","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[{"name":"Zhejiang Hospital, Department of Hematology, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7713-6262","authenticated-orcid":false,"given":"Xinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Institute of Nutrition and Food Safety, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41408-023-00853-3","article-title":"Global Burden of Hematologic Malignancies and Evolution Patterns over the Past 30 Years","volume":"13","author":"Zhang","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating Morphologic, Clinical, and Genomic Data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian Randomization: Genetic Anchors for Causal Inference in Epidemiological Studies","volume":"23","author":"Hemani","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): Explanation and Elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41588-022-01270-1","article-title":"Genomic Atlas of the Plasma Metabolome Prioritizes Metabolites Implicated in Human Diseases","volume":"55","author":"Chen","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/ng.2982","article-title":"An Atlas of Genetic Influences on Human Blood Metabolites","volume":"46","author":"Shin","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen Provides Genetic Insights from a Well-Phenotyped Isolated Population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian Randomisation Studies: A Guide, Glossary, and Checklist for Clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nature08617","article-title":"Cancer-Associated IDH1 Mutations Produce 2-Hydroxyglutarate","volume":"462","author":"Dang","year":"2009","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ebiom.2015.05.022","article-title":"Is Cancer a Genetic Disease or a Metabolic Disease?","volume":"2","author":"Wishart","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.31557\/APJCP.2022.23.4.1107","article-title":"Association of Somatic Gene Mutations with Risk of Transformation into Acute Myeloid Leukemia in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis","volume":"23","author":"Sutandyo","year":"2022","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1158\/1078-0432.CCR-16-2628","article-title":"Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis","volume":"23","author":"Xu","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1182\/blood-2023-190833","article-title":"Purine Metabolism Modulates Leukemia Stem Cell Maintenance in MLL-Rearranged Acute Leukemia","volume":"142","author":"Shi","year":"2023","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101592","DOI":"10.1016\/j.xcrm.2024.101592","article-title":"A CD36-Dependent Non-Canonical Lipid Metabolism Program Promotes Immune Escape and Resistance to Hypomethylating Agent Therapy in AML","volume":"5","author":"Guo","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/cas.13500","article-title":"Monitoring Tyrosine Kinase Inhibitor Therapeutic Responses with a Panel of Metabolic Biomarkers in Chronic Myeloid Leukemia Patients","volume":"109","author":"Yang","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.stem.2018.12.005","article-title":"Venetolax with Azacitidine Drains Fuel from AML Stem Cells","volume":"24","author":"Nakada","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41591-018-0233-1","article-title":"Venetoclax with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Patients with Acute Myeloid Leukemia","volume":"24","author":"Pollyea","year":"2018","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1172\/JCI38942","article-title":"Pharmacologic Inhibition of Fatty Acid Oxidation Sensitizes Human Leukemia Cells to Apoptosis Induction","volume":"120","author":"Samudio","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/s43018-020-00126-z","article-title":"Fatty Acid Metabolism Underlies Venetoclax Resistance in Acute Myeloid Leukemia Stem Cells","volume":"1","author":"Stevens","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.cell.2016.08.057","article-title":"Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia","volume":"167","author":"Sykes","year":"2016","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s43018-022-00331-y","article-title":"Pharmacological Targeting of MTHFD2 Suppresses Acute Myeloid Leukemia by Inducing Thymidine Depletion and Replication Stress","volume":"3","author":"Bonagas","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s44324-024-00005-6","article-title":"MTHFD2 in Healthy and Cancer Cells: Canonical and Non-Canonical Functions","volume":"2","author":"Sdelci","year":"2024","journal-title":"npj Metab. Health Dis."},{"key":"ref_27","first-page":"76","article-title":"Studies on the Genotoxicity and Inhibitory Effect on Gap Junction Intercellular Communication of Bile Acid","volume":"10","author":"Liang","year":"1998","journal-title":"Carcinog. Teratog. Mutagen."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.cmet.2025.01.011","article-title":"AKR1D1 Suppresses Liver Cancer Progression by Promoting Bile Acid Metabolism-Mediated NK Cell Cytotoxicity","volume":"37","author":"Wei","year":"2025","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1111\/j.1349-7006.1998.tb00510.x","article-title":"Lithocholic Acid, a Putative Tumor Promoter, Inhibits Mammalian DNA Polymerase \u03b2","volume":"89","author":"Ogawa","year":"1998","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kov\u00e1cs, P., Csonka, T., Kov\u00e1cs, T., S\u00e1ri, Z., Ujlaki, G., Sipos, A., Kar\u00e1nyi, Z., Sze\u0151cs, D., Heged\u0171s, C., and Uray, K. (2019). Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer. Cancers, 11.","DOI":"10.3390\/cancers11091255"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.chom.2021.07.013","article-title":"A Bacterial Bile Acid Metabolite Modulates Treg Activity through the Nuclear Hormone Receptor NR4A1","volume":"29","author":"Li","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.molmed.2021.12.006","article-title":"Crosstalk between Bile Acid-Activated Receptors and Microbiome in Entero-Hepatic Inflammation","volume":"28","author":"Thibaut","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41586-019-1785-z","article-title":"Bile Acid Metabolites Control TH17 and Treg Cell Differentiation","volume":"576","author":"Hang","year":"2019","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1124\/dmd.114.059709","article-title":"Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)","volume":"42","author":"Squirewell","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/toxsci\/kfn268","article-title":"Bile Acid Sulfation: A Pathway of Bile Acid Elimination and Detoxification","volume":"108","author":"Alnouti","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00253-016-8006-6","article-title":"Interaction of Gut Microbiota with Bile Acid Metabolism and Its Influence on Disease States","volume":"101","author":"Staley","year":"2017","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/s41586-020-2396-4","article-title":"A Metabolic Pathway for Bile Acid Dehydroxylation by the Gut Microbiome","volume":"582","author":"Funabashi","year":"2020","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1182\/blood-2018-06-855221","article-title":"Azacitidine with or without Eltrombopag for First-Line Treatment of Intermediate- or High-Risk MDS with Thrombocytopenia","volume":"132","author":"Dickinson","year":"2018","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic Acid Defines a Novel Class of HDAC Inhibitors Inducing Differentiation of Transformed Cells","volume":"20","author":"Gottlicher","year":"2001","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.leukres.2007.03.012","article-title":"Downregulation of C-Myc Is Critical for Valproic Acid-Induced Growth Arrest and Myeloid Differentiation of Acute Myeloid Leukemia","volume":"31","author":"Cheng","year":"2007","journal-title":"Leuk. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1080\/15592294.2016.1187350","article-title":"Molecular Dissection of Valproic Acid Effects in Acute Myeloid Leukemia Identifies Predictive Networks","volume":"11","author":"Lang","year":"2016","journal-title":"Epigenetics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1158\/0008-5472.CAN-04-3011","article-title":"Valproic Acid Stimulates Proliferation and Self-Renewal of Hematopoietic Stem Cells","volume":"65","author":"Bug","year":"2005","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"542","DOI":"10.3324\/haematol.10758","article-title":"Effect of Histone Deacetylase Inhibitor Valproic Acid on Progenitor Cells of Acute Myeloid Leukemia","volume":"92","author":"Bug","year":"2007","journal-title":"Haematologica"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5860","DOI":"10.1021\/ja5014344","article-title":"Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand","volume":"136","author":"McLuckie","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e180069","DOI":"10.1172\/JCI180069","article-title":"Distinct Landscape and Clinical Implications of Therapy-Related Clonal Hematopoiesis","volume":"134","author":"Takahashi","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.toxrep.2023.01.010","article-title":"Comparative Analysis of Chlorambucil-Induced DNA Lesion Formation and Repair in a Spectrum of Different Human Cell Systems","volume":"10","author":"Krassnig","year":"2023","journal-title":"Toxicol. Rep."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/11\/719\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:18:39Z","timestamp":1762319919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/11\/719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":46,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["metabo15110719"],"URL":"https:\/\/doi.org\/10.3390\/metabo15110719","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2025,11,3]]}}}