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, MnO₂ nanoflowers (MnO₂Nfs) 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, MnO₂Nfs demonstrate high efficiency in effectively eliminating diverse reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂), superoxide anion (O₂ ^•-), and hydroxyl radical (•OH). Through in vitro experiments, it is demonstrated that MnO₂Nfs significantly enhance the recovery of intracellular glutathione content, acting as a potent inhibitor of ferroptosis even in the presence of ferroptosis activators. Moreover, MnO₂Nfs 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 MnO₂Nfs and hold great promise as an innovative and potential clinical therapy for DILI and other ROS-related liver diseases.

Keywords: MnO2 multinanozyme; drug‐induced liver injury (DILI); ferritinophagy; ferroptosis; oxygen species (ROS).