LCAT Deficiency Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance by Promoting Triglyceride Catabolism and Fatty Acid Oxidation

Min Xu; Peiyi Xie; Shaoqing Liu; Xukang Gao; Shiguang Yang; Zhiqiu Hu; Yue Zhao; Yong Yi; Qiongzhu Dong; Christiane Bruns; Xiaoni Kong; Mien-Chie Hung; Ning Ren; Chenhao Zhou

doi:10.1016/j.canlet.2025.217469

LCAT Deficiency Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance by Promoting Triglyceride Catabolism and Fatty Acid Oxidation

Cancer Lett. 2025 Jan 20:217469. doi: 10.1016/j.canlet.2025.217469. Online ahead of print.

Authors

Min Xu¹, Peiyi Xie¹, Shaoqing Liu¹, Xukang Gao¹, Shiguang Yang², Zhiqiu Hu², Yue Zhao³, Yong Yi¹, Qiongzhu Dong⁴, Christiane Bruns³, Xiaoni Kong⁵, Mien-Chie Hung⁶, Ning Ren⁷, Chenhao Zhou⁸

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China.
² Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, P.R. China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, P.R. China; Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, P.R. China.
³ Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Kerpener Straße 62, 50937, Cologne, Germany.
⁴ Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, P.R. China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, P.R. China.
⁵ Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: xiaoni-kong@126.com.
⁶ Graduate Institute of Biomedical Sciences and Research Centers for Cancer Biology and Molecular Medicine, China Medical University, Taichung, Taiwan. Electronic address: mhung@cmu.edu.tw.
⁷ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China. Electronic address: ren.ning@zs-hospital.sh.cn.
⁸ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China. Electronic address: zhouchenhao@fudan.edu.cn.

PMID: 39842501
DOI: 10.1016/j.canlet.2025.217469

Abstract

Lecithin cholesterol acyltransferase (LCAT), a crucial enzyme in lipid metabolism, plays important yet poorly understood roles in tumours, especially in hepatocellular carcinoma (HCC). In this study, our investigation revealed that LCAT is a key downregulated metabolic gene and an independent risk factor for poor prognosis in patients with HCC. Functional experiments showed that LCAT inhibited HCC cell proliferation, migration and invasion. Mechanistically, LCAT interacts with caveolin-1 (CAV1) to promote the binding of CAV1 to PRKACA and inhibit its phosphorylation, thereby inhibiting triglyceride (TAG) catabolism. On the other hand, LCAT inhibits fatty acid oxidation (FAO) by interacting with CPT1A to promote its ubiquitination and degradation. These events result in an inadequate supply of raw materials and energy and inhibit the malignant behaviours of HCC cells. In addition, LCAT is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients, and the inhibition of FAO can increase lenvatinib sensitivity in patients with LCAT^low HCC. This study revealed that LCAT plays a critical role in the regulation of lipid metabolic reprogramming and is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients.

Keywords: Fatty acid oxidation; Hepatocellular carcinoma; LCAT; Lenvatinib; Lipolysis.