Endoplasmic Reticulum-Targeting Natural Compounds: A Novel Frontier in Alleviating Liver Fibrosis

Liver fibrosis, a reversible yet critical stage in chronic liver disease progression, poses a significant global health burden with limited therapeutic options. This review comprehensively explores the molecular mechanisms of endoplasmic reticulum (ER) stress and its dual role in both parenchymal and non-parenchymal cells during liver fibrosis, alongside the therapeutic potential of natural compounds that target ER stress to alleviate fibrosis. Emerging evidence underscores ER stress and oxidative stress as pivotal drivers of hepatic fibrogenesis, primarily through activating hepatic stellate cells (HSCs). We systematically summarize a wide array of natural compounds, from polyphenols to terpenoids, that demonstrate potent anti-fibrotic effects by either ameliorating maladaptive ER stress in hepatocytes or selectively inducing pro-apoptotic ER stress in activated HSCs. Despite their promise, the clinical translation of these compounds is hampered by poor bioavailability and non-specific targeting. We highlight the groundbreaking potential of biomimetic nano-delivery systems, such as cell membrane-camouflaged nanoparticles, to overcome these barriers, offering precise targeting and enhanced therapeutic efficacy. Finally, we discuss current challenges and future directions, advocating for interdisciplinary efforts to advance ER stress-targeting strategies from bench to bedside.