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In this study, a single regulatory mechanism of small molecule kinase inhibitors, with crizotinib as the representative drug is elucidated. First, it is discovered that crizotinib induced aberrant lipid metabolism and apoptosis in the liver. A mechanistic study revealed that crizotinib treatment promoted the accumulation of squalene epoxidase (SQLE) by inhibiting autophagosome\u2010lysosome fusion which blocked the autophagic degradation of SQLE. A maladaptive increase in SQLE led to disturbances in cholesterol and sphingolipid metabolism via an enzymatic activity\u2010dependent manner. Abnormal cholesterol results in both steatosis and inflammatory infiltration, and disturbances in sphingolipid metabolism promote cell apoptosis by inducing lysosomal membrane permeabilization. The restoration of the level or activity of SQLE ameliorated steatosis and hepatocyte injury. The autophagy activator known as metformin or the SQLE enzymatic inhibitor known as terbinafine has potential clinical use for alleviating crizotinib hepatotoxicity.<\/jats:p>","DOI":"10.1002\/advs.202414923","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T12:14:36Z","timestamp":1737461676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Disturbing Cholesterol\/Sphingolipid Metabolism by Squalene Epoxidase Arises Crizotinib Hepatotoxicity"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-7212","authenticated-orcid":false,"given":"Hao","family":"Yan","sequence":"first","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 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