Background and aimsThe accumulation of misfolded proteins, encoded by genetic variants of functional genes leads to Endoplasmic Reticulum (ER) stress, which is a critical consequence in human disorders such as familial hypercholesterolemia, cardiovascular and hepatic diseases. In addition to the identification of ER stress as a contributing factor to pathogenicity, extensive studies on the role of oxidized Low-Density Lipoprotein (oxLDL) and its ill effects in expediting cardiovascular diseases and other metabolic comorbidities are well documented. However, the current understanding of its role in hepatic insults needs to be revised. This study elucidates the molecular mechanisms underlying the progression of oxLDL and ER stress-induced cytotoxicity in HepG2.MethodsHepG2 cells stably expressing wild-type Low-Density lipoprotein receptor (WT-LDLR) and missense variants of LDLR that are pathogenically associated with familial hypercholesterolemia were used as the in vitro models. The relative mRNA expression and protein profiles of ER stress sensors, inflammatory and apoptotic markers, together with cytotoxic assays and measurement of mitochondrial membrane potential, were carried out in HepG2 cells treated with 100 µg per ml oxLDL for 24 to 48 h. 1-way or 2-way ANOVA was used for statistical analyses of datasets.ResultsER stress responses are elicited along all three arms of the unfolded protein response (UPR), with adverse cytotoxic and inflammatory responses in oxLDL-treated conditions.Interestingly, oxLDL-treated ER-stressed HepG2 cells manifested intriguingly low expression of BiP- the master regulator of ER stress, as observed earlier by various researchers in liver biopsies of Non-Alcoholic Steatohepatitis (NASH) patients. This study shows that overexpression of BiP rescues hepatic cells from cytotoxic and inflammatory mechanisms instigated by ER stress in combination with oxLDL, along the ER and mitochondrial membrane and restores cellular homeostasis.ConclusionThe data provide interesting leads that identify patients with familial hypercholesterolemia conditions and potentially other Endoplasmic Reticulum Associated Degradation (ERAD) diseases as highly susceptible to developing hepatic insults with molecular signatures like those manifested in Non-Alcoholic Fatty Liver Disease (NAFLD) and NASH.Limitations and future perspectivesAlthough the use of HepG2 cells as the model is a major caveat of the study, the findings of this research may be used as the pilot study to expand further investigations in primary hepatocytes or iPSC- derived cellular models.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12944-023-01835-x.