biostudies-literatureUnknown88Yang SHepatic 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, genRedox biology103905https://www.ebi.ac.uk/biostudies/studies/S-EPMC12637262biostudies-literatureIntegrated stress response-mediated metabolic reprogramming drives hepatic stellate cell activation and liver fibrosis via the noncanonical EIF3d-ATF4-S100P signaling pathway.PMC12637262Liu XLi YChen ZZhang HNie ZZai WChen WSun XYang SKong YWang ZGao SfalseIntegrated 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, gen2025-01-01T00:00:00Z2025 Oct2026-06-05T19:46:29.086Z2026-05-21T03:11:55.294ZS-EPMC126372624119718310.1016/j.redox.2025.103905