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In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)\u2013proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis.<\/jats:p>","DOI":"10.3390\/ijms252011289","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T03:57:09Z","timestamp":1729483029000},"page":"11289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["6-Gingerol Inhibits De Novo Lipogenesis by Targeting Stearoyl-CoA Desaturase to Alleviate Fructose-Induced Hepatic Steatosis"],"prefix":"10.3390","volume":"25","author":[{"given":"Pan","family":"Li","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Qiu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing 400016, China"},{"name":"School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Yu","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1002\/hep.30908","article-title":"Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation","volume":"71","author":"Chen","year":"2020","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Fernando, D.H., Forbes, J.M., Angus, P.W., and Herath, C.B. 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