Abstract Avasimibe, a cholesterol-lowering drug with proven safety in clinical trials, has also been repositioned as an anticancer agent in various preclinical investigations. A study from our group reported that hypercholesterolemia promotes hepatocellular carcinoma (HCC) cell survival and impairs the cytotoxic effect of sorafenib, a kinase inhibitor. In the present study, we demonstrate that under hypercholesterolemic conditions, the anticancer efficacy of sorafenib in HCC is enhanced by co-treatment with avasimibe. To elucidate the role of hypercholesterolemia in sorafenib efficacy, both in vitro and in vivo models of HCC were used. In vitro, co-treatment with both drugs synergistically inhibited HCC cell viability and induced cell death under both normal and hypercholesterolemic conditions. At the molecular level, the downregulation of extracellular signal-regulated kinase signaling and the induction of endoplasmic reticulum stress are likely to contribute to the combinatorial cytotoxic effect of sorafenib and avasimibe in vitro. In mice fed on a high-cholesterol diet, the efficacy of sorafenib was restored by co-administration of avasimibe. Collectively, these findings suggest that the reduction in sorafenib efficacy is due to a hypercholesterolemic phenotype that can be restored by avasimibe co-treatment, with implications for treatment strategy. Graphical abstract Schematic representation. Hypercholesterolemia reduces SORA cytotoxicity in HCC cells by diminishing its intracellular accumulation and cytotoxicity. Co-treatment with SORA and AVA in HCC cells under hypercholesterolemia induces HCC cell death, which is associated with a reduction in ERK signaling and induction of ER stress. Research highlights <UnorderedList Mark="Bullet"> <ItemContent> Cholesterol impedes sorafenib efficacy in Hepatocellular carcinoma cells. </ItemContent> <ItemContent> Avasimibe restores the functionality of sorafenib under a hypercholesterolemic environment. </ItemContent> <ItemContent> Combination of sorafenib and avasimibe synergistically enhances cytotoxicity in hepatocellular carcinoma. </ItemContent> <ItemContent> Sorafenib and avasimibe treatment in the presence of LDLc.is associated with diminished ERK activation and increased ER stress. </ItemContent> </UnorderedList>

Hypercholesterolemia-induced impairment in sorafenib functionality is overcome by avasimibe co-treatment

期刊论文
发表日期：

2026年5月15日

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Dipti Athavale,
Himanshi Yaduvanshi,
Firoz Khan Bhati,
Shyamananda Singh Mayengbam,
Tushar H More,
Srikanth Rapole,
Manoj Kumar Bhat

摘要

Abstract

Avasimibe, a cholesterol-lowering drug with proven safety in clinical trials, has also been repositioned as an anticancer agent in various preclinical investigations. A study from our group reported that hypercholesterolemia promotes hepatocellular carcinoma (HCC) cell survival and impairs the cytotoxic effect of sorafenib, a kinase inhibitor. In the present study, we demonstrate that under hypercholesterolemic conditions, the anticancer efficacy of sorafenib in HCC is enhanced by co-treatment with avasimibe. To elucidate the role of hypercholesterolemia in sorafenib efficacy, both in vitro and in vivo models of HCC were used. In vitro, co-treatment with both drugs synergistically inhibited HCC cell viability and induced cell death under both normal and hypercholesterolemic conditions. At the molecular level, the downregulation of extracellular signal-regulated kinase signaling and the induction of endoplasmic reticulum stress are likely to contribute to the combinatorial cytotoxic effect of sorafenib and avasimibe in vitro. In mice fed on a high-cholesterol diet, the efficacy of sorafenib was restored by co-administration of avasimibe. Collectively, these findings suggest that the reduction in sorafenib efficacy is due to a hypercholesterolemic phenotype that can be restored by avasimibe co-treatment, with implications for treatment strategy.

Graphical abstract

Schematic representation. Hypercholesterolemia reduces SORA cytotoxicity in HCC cells by diminishing its intracellular accumulation and cytotoxicity. Co-treatment with SORA and AVA in HCC cells under hypercholesterolemia induces HCC cell death, which is associated with a reduction in ERK signaling and induction of ER stress.

Research highlights

Cholesterol impedes sorafenib efficacy in Hepatocellular carcinoma cells.

Avasimibe restores the functionality of sorafenib under a hypercholesterolemic environment.

Combination of sorafenib and avasimibe synergistically enhances cytotoxicity in hepatocellular carcinoma.

Sorafenib and avasimibe treatment in the presence of LDLc.is associated with diminished ERK activation and increased ER stress.