Multienzyme Active Manganese Oxide Alleviates Acute Liver Injury by Mimicking Redox Regulatory System and Inhibiting Ferroptosis

Abstract Drug‐induced liver injury (DILI) is a severe condition characterized by impaired liver function and the excessive activation of ferroptosis. Unfortunately, there are limited options currently available for preventing or treating DILI. In this study, MnO 2 nanoflowers (MnO 2 Nfs) with remarkable capabilities of mimicking essential antioxidant enzymes, including catalase, superoxide dismutase (SOD), and glutathione peroxidase are successfully synthesized, and SOD is the dominant enzyme among them by density functional theory. Notably, MnO 2 Nfs demonstrate high efficiency in effectively eliminating diverse reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ), superoxide anion (O 2 •− ), and hydroxyl radical (•OH). Through in vitro experiments, it is demonstrated that MnO 2 Nfs significantly enhance the recovery of intracellular glutathione content, acting as a potent inhibitor of ferroptosis even in the presence of ferroptosis activators. Moreover, MnO 2 Nfs exhibit excellent liver accumulation properties, providing robust protection against oxidative damage. Specifically, they attenuate acetaminophen‐induced ferroptosis by inhibiting ferritinophagy and activating the P62‐NRF2‐GPX4 antioxidation signaling pathways. These findings highlight the remarkable ROS scavenging ability of MnO 2 Nfs and hold great promise as an innovative and potential clinical therapy for DILI and other ROS‐related liver diseases.