Fig 9. Schematic diagram depicting the mechanistic details of exacerbated liver fibrosis by MASH diet plus alcohol binge.

(A) Briefly, alcohol binges in MASH diet fed mice lead to increased neutrophil infiltration and NETs formation in NLRP3-depedent manner. NETs are sensed by monocytes and hepatic stellate cells via NLRP3 which promotes IL-1β production from monocytes and increases α-SMA and Collagen1 production from hepatic stellate cells. Activation of hepatic stellate cells and pro-inflammatory cytokine production from monocytes promotes liver damage and fibrosis. Neutrophil depletion by anti-Ly6G antibody, NETs disruption by DNase, and NLRP3 inhibition by MCC950, ameliorates liver damage and fibrosis. (B) NETs are sensed by hepatic stellate cells by NLRP3, which promotes IL-1β production from stellate cells. NLRP3 and IL-1β increase α-SMA production from hepatic stellate cells. Activation of hepatic stellate cells promotes fibrosis. Disrupting NETs by DNase, inhibiting NLRP3 by MCC950, or blocking IL-1β by IL-1 receptor antagonist attenuates α-SMA production from hepatic stellate cells and reduces fibrosis.