Shifting cell death modes in hepatic steatosis: from apoptosis to necroptosis

In the liver, hepatocyte death occurs during the regeneration process following injury. While hepatocyte death triggers regeneration through hepatocyte proliferation in the non-steatotic liver, it impairs this process in the steatotic liver. Both the number and mode of hepatocyte death during regeneration change in the steatotic liver, affecting regeneration and thereby contributing to the progression of acute liver injury and metabolic dysfunction-associated steatotic liver disease (MASLD). Apoptosis, a non-inflammatory mode of cell death, predominantly occurs during liver regeneration. As hepatic steatosis progresses, sporadic and scattered apoptotic cell death increases, leading to delayed regeneration. In severe steatotic livers undergoing regeneration, the mode of cell death shifts to pro-inflammatory necroptosis. This transition leads to inflammation around the dead hepatocytes, resulting in zonal hepatocyte death and further impairing regeneration, thus exacerbating acute liver injury and MASLD. The integrated stress response (ISR), mediated by phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α), plays a crucial role in regulating hepatocyte death during steatotic liver regeneration. The ISR-induced transcription factor C/EBP homologous protein (CHOP) promotes apoptosis, thereby delaying regeneration. When ISR is further enhanced, activating transcription factor 3 (ATF3) is upregulated, inducing the expression of receptor-interacting protein kinase 3 (RIPK3), which shifts cell death mode from apoptosis to necroptosis. While treatments for MASLD targeting apoptosis have shown limited success, future therapies targeting necroptosis and its regulatory molecules may provide novel therapeutic strategies.