Metabolic-associated
fatty liver disease (MAFLD) is currently one
of the main causes of chronic liver disease, but its potential mechanism
remains unclear. This study proved that estrogen receptor α
(ERα) could negatively control hepatocyte pyroptosis by inhibiting
NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome
activation, gasdermin D (GSDMD)-N generation, propidium iodide (PI)
uptake, lactate dehydrogenase (LDH) release, and pro-inflammatory
cytokine (IL-1β and IL-18) release. Furthermore, inhibition
of pyroptosis ameliorated ERα deletion-induced metabolic dysfunction,
insulin resistance, and liver injury. Mechanistically, ERα was
confirmed to inhibit pyroptosis by directly interacting with GSDMD,
and GSDMD blockade reversed the ERα inhibition-induced pyroptosis
and improved lipid accumulation in hepatocytes. Notably, the treatment
of wild-type (WT) mice with genistein, a phytoestrogen, could attenuate
high-fat diet (HFD)-induced liver lipid steatosis and inhibit NLRP3–GSDMD-mediated
pyroptosis. Results provide new insights into the underlying mechanism
of pyroptosis regulation and uncover the potential treatment target
of MAFLD.
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