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BACKGROUND:Hepatocellular carcinoma (HCC) is associated with endoplasmic reticulum (ER) stress and lipid metabolism disruption. Doxorubicin (DOX), a common treatment for HCC, and ER-stress can alter lipid composition of the tumour, contributing to tumorigenesis.AIM: to determine the role of inositol requiring enzyme-1 alpha (IRE1α) on lipid metabolism and response to DOX in HCC.METHODS:HepG2 cells and a diethylnitrosamine-induced HCC mouse model were treated with 4μ8C (IRE1α inhibitor), DOX or combination (4μ8C+DOX). Lipid accumulation in tumour was assessed by quantification of liver triglycerides (TGs) levels in mouse tissue. In HepG2 cells, Oil Red staining was used to detect lipid droplets and expression of lipid metabolic markers (adipose triglyceride lipase (ATGL), monoacylglycerol lipase (MGL) and lysosomal acid lipase (LAL)) was measured by RT-qPCR. Seahorse analysis was used to determine the oxygen consumption rate (OCR) in HepG2 cells under the effect of the treatments. ANOVA tests were applied for statistical analysis (p<0.05).RESULTS:Treatment with 4μ8C+DOX decreased TG enrichment in tumours from mice and reduced lipid droplet accumulation in HepG2 cells. ATGL, MGL and LAL mRNA expression was increased after treatment with DOX, but this was reverted to control levels after treating HepG2 cells with 4μ8C+DOX. Cell metabolism was increased (higher OCR levels) after treatment with DOX and 4μ8C+DOX in HepG2 cells.CONCLUSION: Inhibition of IRE1α ER-stress pathway combined with DOX treatment may reduce lipid accumulation in liver tumours from mice and HepG2 cells, potentially contributing to an improved cancer therapy. However, the underlying mechanisms of these observations need to be further investigated.