PGC-1α protects against MASH via Tim23-dependent inhibition of DRP1-mediated ferroptosis

Peroxisome Proliferator-activated Receptor gamma coactivator 1α (PGC-1α) is crucial for mitochondrial function and biogenesis. However, whether and how PGC-1α can regulate hepatocyte Ferroptosis during the pathogenic process of metabolic dysfunction-associated steatohepatitis (MASH) has not been clarified. Hepatocyte Ferroptosis was assessed in the liver of MASH patients and in vivo and in vitro MASH models. The mechanisms by which PGC-1α regulated hepatocyte Ferroptosis during the process of MASH were examined by Western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, luciferase reporter, and co-immunoprecipitation assays. Hepatocyte Ferroptosis, down-regulated Tim23 and up-regulated ACSL4 expression were observed in the livers of MASH patients, and in vivo and in vitro MASH models. PGC-1α deficiency exacerbated hepatocyte Ferroptosis in mouse models of MASH induced by high-fat diet and methionine- and choline-deficient diet, and primary mouse hepatocytes that had been treated with palmitic acid. Conversely, PGC-1α over-expression mitigated hepatocyte Ferroptosis in these models. Mechanistically, PGC-1α promoted the binding of nuclear respiratory factor (Nrf)1 to the Tim23 promoter, reducing Drp1 transcription and ACSL4 mitochondrial translocation, inhibiting hepatocyte Ferroptosis and MASH. These findings indicated that PGC-1α inhibited hepatocyte Ferroptosis and attenuated MASH by upregulating Tim23 and inhibiting the Drp1-ACSL4 axis.