{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:17:15Z","timestamp":1787833035751,"version":"build-2784847793"},"reference-count":58,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"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":"publisher","award":["82405062"],"award-info":[{"award-number":["82405062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82405062"],"award-info":[{"award-number":["82405062"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Drug-induced liver injury (DILI) remains a leading contributor to acute liver failure, yet phenotypic classification still relies on the R-value, leaving the mixed-pattern (MD) subtype a heterogeneous category between hepatocellular (HD) and cholestatic (CD) injury. We aimed to identify a metabolic signature that helps resolve this heterogeneity. Methods: Targeted LC-MS\/MS metabolomics was performed on 79 patients with DILI (HD = 54, CD = 7, MD = 18) and 221 healthy controls. A 32-metabolite panel was used to train an XGBoost classifier with pre-specified, fold-invariant hyperparameters, evaluated via Leave-One-Out Cross-Validation and interpreted by TreeExplainer-based SHAP attribution. Results: SHAP identified 5\u2032-methylthioadenosine (MTA) as the dominant contributor. A four-parameter logistic fit of its SHAP dependence curve gave an exploratory, model-derived transition point at a relative abundance of 93. Applying this value to the 18 held-out MD patients assigned 16 to a hepatocellular and 2 to a cholestatic trajectory. MTA correlated with total bilirubin (r = 0.53, p &lt; 0.001) but not ALT (r = \u22120.19, p = 0.10), dissociating it from hepatocyte leakage. Conclusions: MTA emerges as an exploratory biomarker that uncovers the distinct metabolic trajectories hidden within mixed-pattern DILI. Furthermore, these findings highlight the MTA-methylthioadenosine phosphorylase (MTAP) axis as a potential mechanistic driver of cholestatic injury.<\/jats:p>","DOI":"10.3390\/metabo16090614","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:58:21Z","timestamp":1787828301000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomics and Machine Learning Uncover 5\u2032-Methylthioadenosine as a Metabolic Indicator of Mixed-Pattern Drug-Induced Liver Injury"],"prefix":"10.3390","volume":"16","author":[{"given":"Jinghui","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingrong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Beijing Youan Hospital, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongcai","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Youan Hospital, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0059-2284","authenticated-orcid":false,"given":"Xian","family":"Ding","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoling","family":"An","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41572-019-0105-0","article-title":"Drug-induced liver injury","volume":"5","author":"Andrade","year":"2019","journal-title":"Nat. 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