Integrated stress response-mediated metabolic reprogramming drives hepatic stellate cell activation and liver fibrosis via the noncanonical EIF3d-ATF4-S100P signaling pathway

Hepatic stellate cells (HSCs) trans-differentiation into myofibroblasts is central to liver fibrosis. Integrated stress response (ISR) signaling, including metabolic stress, plays a critical role in this process. However, the precise role of ISR signaling in HSCs activation-whether detrimental or protective-remains unclear. Here we identified that the noncanonical cap-binding protein EIF3d-mediated ATF4 expression is significantly upregulated in HSCs from both patients and mouse models of fibrotic livers, with its levels positively correlating with the degree of fibrosis. EIF3d-ATF4 signaling was induced by TGFβ1 in HSCs and was demonstrated to be both necessary and sufficient for promoting HSC survival, proliferation, activation, and extracellular matrix (ECM) production. Furthermore, genetic and pharmacological inhibition of EIF3d-ATF4 effectively prevented TGFβ1-induced HSC activation by suppressing mitochondrial activity and glycolysis. Mechanistically, EIF3d-ATF4 overexpression drove ATF4-dependent S100P transcription, which facilitated metabolic reprogramming and upregulated fibrogenic markers. This EIF3d-ATF4-S100P axis promoted liver fibrosis by activating JNK and NLRP3 signaling in HSCs, thereby inducing HSC activation and conferring resistance to apoptosis. Importantly, mice with HSC-specific ATF4 deletion or treated with our innovative ISR antagonist, ERMT1, were protected from three distinct mouse fibrotic models. These findings underscore the role of the EIF3d-ATF4-S100P signaling axis in liver fibrosis progression and HSC activation, presenting it as a promising therapeutic target for managing liver fibrosis and cirrhosis.