ARID5A Is a PERK-Dependent Effector of the Endoplasmic Reticulum Stress Response That Protects Against Steatohepatitis

Abstract

Lipotoxic endoplasmic reticulum (ER) stress is a fundamental feature of metabolic dysfunction-associated steatohepatitis (MASH). ER stress activates adaptive signaling processes that aim to restore ER homeostasis. Yet, depending on the duration, magnitude, and cellular context, sustained ER stress becomes maladaptive and leads to cell death. The regulatory pathways that determine adaptive versus maladaptive ER stress outcomes remain incompletely understood. Here we integrated transcriptomic and chromatin-accessibility analyses in complementary models of proteotoxic and lipotoxic ER stress to identify previously unrecognized regulators of the ER stress response. These analyses identified the dual DNA- and RNA-binding protein AT-rich interaction domain 5A (ARID5A) as an ER stress-responsive gene. ARID5A protein was abundantly expressed in hepatocytes, and ARID5A mRNA and protein were upregulated in palmitate-induced lipotoxic ER stress across multiple hepatocyte models. Using complementary genetic and pharmacological approaches, we demonstrated that ARID5A induction was independent of IRE1 and ATF6 signaling and was attenuated by inhibition of the PERK pathway. To determine the functional relevance of ARID5A in MASH, we employed hepatocyte-directed AAV9-mediated ARID5A overexpression in mice fed a MASH-inducing diet. ARID5A overexpression attenuated steatohepatitis, inflammation, and fibrosis. Together, these findings identify ARID5A as a previously unrecognized PERK-dependent effector of the hepatocyte ER stress response and demonstrate that increasing hepatocyte ARID5A is protective in experimental MASH. This work provides a foundation for defining the mechanisms by which ARID5A regulates hepatocyte stress responses and MASH severity.