Gallium‐Doped MXene Nanozymes Protect Liver Through Multi‐Death Pathway Blockade and Hepatocyte Regeneration

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.