Abstract
Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is the fifth most prevalent cancer worldwide and second leading cause of cancer-related deaths, underscoring its grim prognosis. Key risk factors for HCC include HBV, HCV, cirrhosis, inherited metabolic diseases, vitamin supplementation, heavy alcohol use, obesity etc. Despite the well-documented impact of alcohol on HCC, there remains a significant gap in understanding alcohol-associated HCC (A-HCC) compared to viral hepatitis associated HCC. So, in this study we tried to elucidate the role of UPR pathway in exacerbating HCC prognosis under the condition of A-HCC. Notably, our RT-qPCR and western blot analysis showed significant upregulation of PERK-ATF4-LAMP3 arm along with CHOP, VEGF-A and nuclear translocation of NF-KB in both HepG2 and Hep3B cell lines. Increased extracellular & intracellular cholesterol and triglyceride levels obtained can be related with the higher expression of SREBP-2 and SREBP-1c respectively. Ethanol exposure also enhanced the invasive and migratory properties of HCC, reduced apoptosis with increased stemness in a PERK dependent manner. Moreover, orally available PERK inhibitor (GSK2606414) successfully relieved the effects caused by ethanol in HepG2 and Hep3B cell lines. In summary, HCC cells gain aggressiveness due to ethanol exposure via PERK/ATF4/LAMP3 pathway, and targeting PERK could serve as a promising therapeutic strategy for A-HCC, mitigating several cancer hallmarks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-37114-9.