Pharmacological Targeting of NRF2 Represents a Promising Therapeutic Approach for Pyroptosis-Related Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by the accumulation of fat within hepatocytes in the absence of excessive alcohol consumption or other identifiable causes of liver injury. As a disease involving complex pathogenic mechanisms, NAFLD has become the most prevalent chronic liver disease and may progress to more severe conditions. Pyroptosis is a pro-inflammatory form of programmed cell death that is distinct from classical apoptosis. Accumulating evidence suggests that pyroptosis plays a role in the pathogenesis of NAFLD, contributing to disease progression from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Excessive activation of pyroptosis can exacerbate inflammatory responses, induce cellular damage, disrupt immune homeostasis, and impair liver function. Therefore, elucidating the mechanisms and roles of pyroptosis in NAFLD is crucial for the development of effective therapeutic strategies. As a key transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2) has emerged as a promising therapeutic target. Pharmacological modulation of NRF2 has shown potential in treating diseases characterized by oxidative stress and inflammation. Findings from in vitro and animal studies suggest that various compounds that target NRF2 to modulate pyroptosis exhibit notable effects on the initiation and progression of NAFLD. Although most of these agents are still in the early stages of preclinical research, they hold substantial promise for future clinical translation. This review outlines recent advances in pyroptosis-related research in NAFLD and highlights pharmacological targeting of NRF2 as a promising therapeutic approach for pyroptosis-mediated NAFLD.