Abstract

Acetaminophen-induced liver injury (AILI) is a major cause of acute liver failure, yet single-target therapies like N-acetylcysteine remain inadequate due to its complex pathogenesis. To address this challenge, we propose a dual-action defense-regeneration strategy that concurrently blocks multi-death pathways and promotes hepatocyte regeneration. Specifically, the therapeutic metal gallium is doped into V 2 C MXene nanozymes (Ga-V 2 C) to surpass conventional nanozymes by integrating sustained antioxidant activity for death signaling blockade, multi-pathway regulation of cell death networks, and activation of pro-regenerative molecules. In vivo, Ga-V 2 C nanozymes exhibited superior protective efficacy over N-acetylcysteine against AILI. Mechanistic investigations revealed that the Ga-V 2 C nanozymes disrupt the synergistic amplification of liver injury by simultaneously inhibiting three key death pathways: oxidative stress (via ROS scavenging, reduce JNK phosphorylation, and activated Nrf2/HO-1), apoptosis (via restored Bcl-2/Bax balance), and ferroptosis (by suppressed iron-dependent lipid peroxidation and upregulated SLC7A11/FTH1/FTL1). Notably, Ga-V 2 C nanozymes fostered a pro-regenerative microenvironment by activating Wnt/βCAT pathways signaling and key cell cycle drivers (CCND1, MYC, PCNA), thereby enhancing hepatocyte regeneration. This work not only offers a promising therapeutic approach for AILI but also significantly expands the scope of nanozyme-based therapeutics for complex diseases requiring multi-target intervention.