Injectable Zn2+-Driven carrier-free hydrogel via self-assembly of natural small molecules for liver fibrosis therapy through concurrent autophagy activation and ferroptosis inhibition

Activation of autophagy represents a critical pathway for eliminating activated hepatic stellate cells (HSCs). However, excessive autophagy induction may trigger ferroptosis, thereby aggravating liver damage. This study proposes synergistic regulation of HSC autophagy and ferroptosis as a novel strategy against liver fibrosis. We engineered an injectable Zn²⁺-coordination supramolecular hydrogel (termed ASA-Gel) through self-assembly of natural bioactive compounds artesunate (ASA) and glycyrrhizic acid (GA) without exogenous carriers. What's more, Zn²⁺ in ASA Gel could significantly reduce the concentration of hydrogel. Molecular dynamics simulations reveal that ASA Gel formation is primarily governed by Zn²⁺-carboxylate coordination bonds and intermolecular hydrogen bonding. In CCl₄-induced fibrotic mice, ASA Gel showed superior efficacy to ASA monotherapy and GA-Zn²⁺ complexes. Molecular profiling revealed that ASA Gel upregulated Atg9A and Atg101 in the liver, thereby promoting autophagosome formation, inhibiting P62 expression, and enhancing autophagic flux. Moreover, ASA Gel significantly promoted the expression of GPX4 and SLC7A11 genes, indicating that it inhibited the ferroptosis process in liver tissue. This work establishes a carrier-free hydrogel platform for spatiotemporally coordinated regulation of autophagy and ferroptosis in HSCs.