Targeting endoplasmic reticulum proteostasis in liver fibrosis: From signaling mechanisms to therapeutic opportunities

Liver fibrosis, a progressive consequence of chronic liver disease, is characterized by excessive extracellular matrix (ECM) deposition and persistent inflammation. It poses a substantial global health burden, particularly among individuals with obesity, excessive alcohol intake, or chronic viral hepatitis. Increasing evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in fibrogenesis by disrupting cellular homeostasis and activating pathological signaling pathways. This review offers a comprehensive overview of the mechanisms driving liver fibrosis, with a particular emphasis on ER stress-associated pathways, including ER-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy. We further discuss the impact of chronic ER stress on hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells (KCs), emphasizing their roles in fibrosis progression. Finally, we explore therapeutic strategies targeting ER stress as potential antifibrotic interventions, providing novel insights into the treatment of liver fibrosis.