Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis

Lipid homeostasis plays a fundamental role in the development of hepatocellular carcinoma (HCC). This study found that a high-fat diet (HFD) increased the expression of sterol O-acyltransferase1 (SOAT1) and carnitine palmitoyltransferase 1A (CPT1A) in diethylnitrosamine-induced HCC. Bioinformatic analysis revealed a double-negative feedback loop between SOAT1-mediated fatty acid storage and CPT1A-mediated fatty acid oxidation (FAO). SOAT1 inhibition enhanced CPT1A protein, promoting fatty acid oxidation, while CPT1A inhibition increased lipid droplet formation via SOAT1. Simultaneous targeting of SOAT1 and CPT1A using avasimibe and etomoxir demonstrated synergistic anti-cancer effects in vitro and in vivo. This research provides new mechanistic insights into lipid homeostasis regulation and proposes a novel combination therapy for HCC.

Meiling Ren, Huanji Xu, Hongwei Xia, Qiulin Tang, Feng Bi