Metformin attenuates colitis via blocking STAT3 acetylation by reducing acetyl-CoA production
Abstract
BACKGROUND AND AIMS: While metformin has been shown to alleviate dextran sulfate sodium (DSS)-induced colitis in murine models, the mechanisms underlying its anti-inflammatory and barrier-restorative effects remain poorly defined. This study investigates the role of acetyl coenzyme A (acetyl-CoA)-dependent STAT3 acetylation in mediating metformin's therapeutic actions, with the goal of identifying novel molecular targets for ulcerative colitis (UC) treatment.
METHODS: Acute colitis was induced in wild-type C57BL/6J mice via oral DSS administration, followed by daily intraperitoneal metformin treatment. Intestinal inflammation, barrier integrity, and STAT3 signaling were assessed using histopathology, western blotting, and transmission electron microscopy. To validate STAT3's critical role in colitis pathogenesis, intestinal epithelium-specific STAT3 knockout mice were employed, enabling targeted investigation of STAT3 acetylation and its regulation by metformin.
RESULTS: Metformin attenuated DSS-induced colitis by suppressing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), reducing epithelial apoptosis, and restoring tight junction proteins (ZO-1, E-cadherin, Occludin). Mechanistically, metformin reduced acetyl-CoA levels, thereby inhibiting STAT3 acetylation and downstream pathway activation. The pivotal role of STAT3 in colitis progression was confirmed using STAT3 knockout mice, as the therapeutic effects of metformin were significantly diminished in the absence of…
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