Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury

Background & Aims Drug-induced liver injury (DILI) is a leading cause of acute liver failure, and treatment of DILI remains a challenge. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream whose physiological role in protection against DILI has not been examined. Methods Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of MG53 or RIPK3. Live cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. Results Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. Conclusions Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. Lay Summary Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to the medical society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver-cell protection.