Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.