Abstract

Liver fibrosis is a progressive pathological process driven by chronic liver injury, with limited effective therapies. Zinc transporter ZIP4 (SLC39A4) is critical for zinc homeostasis, but its role in liver fibrosis remains unclear. Here, we show that ZIP4 expression is significantly downregulated in fibrotic human liver tissues. Using hepatocyte-specific Zip4 knockout and AAV8-mediated ZIP4 overexpression mouse models, we demonstrate that ZIP4 deficiency exacerbates CCl 4 -induced liver injury, fibrosis, oxidative stress, apoptosis, and ferroptosis, whereas ZIP4 overexpression alleviates these lesions. Mechanistically, ZIP4 maintains hepatic zinc homeostasis, upregulates antioxidant enzymes (PRDXs, SODs), and inhibits ferroptosis by regulating p53, SLC7A11, SLC40A1, and GPX4. Furthermore, zinc gluconate (Zn-Glu) combined with GCN2 inhibitor (GCN2iB) synergistically increases ZIP4 expression and intracellular zinc levels in HepG2 cells. In CCl 4 -treated mice, Zn-Glu plus GCN2iB upregulates hepatic ZIP4, enhances antioxidant capacity, suppresses ferroptosis, and mitigates liver fibrosis. Collectively, our findings identify ZIP4 as a novel anti-fibrotic regulator that protects against liver fibrosis by maintaining zinc homeostasis, restraining oxidative stress, and inhibiting ferroptosis. The Zn-Glu/GCN2iB combination exerts anti-fibrotic effects by activating ZIP4 signaling, representing a promising strategy for clinical intervention.