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Cuproptosis, a newly discovered form of cell death induced by copper ions, triggers cytotoxic stress through lipoylated protein oligomerization and may offer a novel therapeutic strategy for liver fibrosis. However, the mechanisms underlying cuproptosis in liver fibrosis are not well understood. During liver fibrosis progression, hepatic stellate cells (HSCs) activate, proliferate, and secrete extracellular matrix components, contributing to fibrosis. Activated HSCs also undergo lipophagy, the degradation of lipid droplets. The study shows that Ras\u2010related protein Rab\u201018 (RAB18), a protein involved in lipid metabolism, inhibits lipophagy, upregulates Carnitine palmitoyltransferase 1A (CPT1A), and promotes succinylation of dihydrolipoamide dehydrogenase (DLD) at site K320, triggering cuproptosis in HSCs. Diallyl trisulfides (DATs), a garlic\u2010derived compound, induces phase separation of RAB18 and promotes mitochondrial\u2010associated membrane structures (MAMs) formation, further accelerating RAB18 phase separation. DATs selectively protects hepatocytes while activating cuproptosis in HSCs. Interfering with RAB18 expression reverses the DATs\u2010induced inhibition of lipophagy and cuproptosis. These findings, confirmed in primary cells, human liver stellate cells (LX2), rodent models and clinical samples, suggest that DATs, by targeting RAB18 and inducing its phase separation, subsequently inhibit lipophagy and promote cuproptosis, making it a promising therapeutic approach for liver fibrosis. [Correction added on 02 May 2025, after first online publication: In line 4 of the abstract, \u201csulfenylated\u201d was updated to \u201clipoylated\u201d.]<\/jats:p>","DOI":"10.1002\/advs.202415325","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T06:34:47Z","timestamp":1744353287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Diallyl Trisulfide From Garlic Regulates RAB18 Phase Separation to Inhibit Lipophagy and Induce Cuproptosis in Hepatic Stellate Cells for Antifibrotic Effects"],"prefix":"10.1002","volume":"12","author":[{"given":"Haoyuan","family":"Tian","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media Nanjing University of Chinese Medicine  Nanjing 210023 China"},{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent 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