Non-alcoholic fatty liver disease (NAFLD), which is a series of diseases including simple fatty liver, nonalcoholic steatohepatitis and cirrhosis, is one of the main causes of liver cirrhosis, carcinoma and liver transplantation. The mechanism of NAFLD is not fully understood. Besides the physical exercise and diet intervention, there is no recognized effective drug therapy for NAFLD. Pyroptosis is a newly discovered type of programmed cell death, which is associated with activation of caspase-1, or caspase-2 mediated inflammasome activation. The main function of inflammasome is to activate caspase-1, which indirectly regulates the expression and secretion of inflammatory factors interleukin-1 and interleukin-18. Recent studies have shown that inflammasome-associated pyroptosis plays a key role in NAFLD. This review will discuss the latest researches in this field to provide new scientific knowledge for prevention and treatment of NAFLD.

Metabolic-associated fatty liver disease (MAFLD), which is previously known as non-alcoholic fatty liver disease (NAFLD), represents a major health concern worldwide with limited therapy. Here, we provide evidence that ferroptosis, a novel form of regulated cell death characterized by iron-driven lipid peroxidation, was comprehensively activated in liver tissues from MAFLD patients. The canonical-GPX4 (cGPX4), which is the most important negative controller of ferroptosis, is downregulated at protein but not mRNA level. Interestingly, a non-canonical GPX4 transcript-variant is induced (inducible-GPX4, iGPX4) in MAFLD condition. The high fat-fructose/sucrose diet (HFFD) and methionine/choline-deficient diet (MCD)-induced MAFLD pathologies, including hepatocellular ballooning, steatohepatitis and fibrosis, were attenuated and aggravated, respectively, in cGPX4-and iGPX4-knockin mice. cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes. Knockdown of iGPX4 by siRNA alleviated lipid stress, ferroptosis and cell injury. Mechanistically, the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress, and thus promotes ferroptosis. Co-immunoprecipitation and nano LC-MS/MS analyses confirmed the interaction between iGPX4 and cGPX4. Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis, and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.