Unfolded Protein Response (UPR) Signaling in Hepatic Stellate Cells (HSC) as a Key Regulator of Liver Fibrosis

Abstract

Liver cirrhosis is a leading cause of death worldwide, with the prevalence of cirrhosis on the rise. Cirrhosis is driven by various etiologies, including liver injuries from diabetes, obesity, metabolic disorders, and alcohol use. Central to the progression of chronic liver disease to cirrhosis is the activation of hepatic stellate cells (HSCs), which secrete extracellular matrix (ECM) proteins such as collagen to form fibrotic scars. Activated HSCs produce vast amounts of fibrotic proteins that require folding and processing prior to secretion. Increased protein folding demands cause endoplasmic reticulum (ER) stress and initiate the Unfolded Protein Response (UPR). The UPR allows HSCs to adapt to ER stress and restore proteostasis to maintain fibrogenic secretion, while failure to restore proteostasis leads to apoptosis. All three arms of the UPR are activated in fibrogenic HSCs, propagated by ATF6α, PERK, and IRE1α, but how activated HSCs manage elevated UPR signaling while remaining viable is not well understood. This gap in knowledge limits therapeutic development to limit fibrosis progression. We identified Protein Kinase R-like ER Kinase (PERK) as a crucial factor for fibrogenesis, but the mechanisms of PERK signaling in HSCs are largely unknown. Our research aims to understand how PERK regulates HSC activation and fibrogenesis and to target these mechanisms in order to promote HSC inactivation and mitigate fibrogenesis. Importantly, we demonstrated that PERK activation stimulates its downstream target, a stress-responsive gene named GADD45A, which serves as a regulator of HSC activation. Finally, we show that HSC-specific deletion of GADD45A limits CCl₄-driven fibrogenesis in vivo with reduced collagen deposition and limited HSC activation, likely through increased HSC senescence. In conclusion, our findings highlight the pivotal role of the PERK–GADD45A axis in limiting liver fibrosis and underscore its potential as a therapeutic target to modulate HSC fate and attenuate fibrogenesis in chronic liver disease.