Arctigenin, a Lignan Ingredient in Burdock, Inhibits Gasdermin D-Mediated Pyroptosis of Colonic Macrophages to Alleviate Ulcerative Colitis by Down-Regulating Fatty Acid Oxidation.

Arctigenin, a lignan ingredient from burdock (Arctium lappa L.), has therapeutic promise against ulcerative colitis. Here, we reveal its mechanism based on pyroptosis of colonic macrophages. The data showed that arctigenin specifically inhibited N-terminal fragment of gasdermin D (GSDMD-N)-mediated pyroptosis of colonic macrophages in mice with dextran sulfate sodium salt-induced colitis. Mechanistically, arctigenin activated estrogen receptor β (ERβ), which bound to the intron region of carnitine palmitoyl transferase 1A (CPT1A) to down-regulate CPT1A expression, thereby reducing fatty acid oxidation (FAO) in macrophages. This reduction in FAO inhibited GSDMD-N acetylation and oligomerization, ultimately attenuating pyroptosis. In colitis mice, overexpression of CPT1 or knockout of ERβ abolished the protective effects of arctigenin. These findings demonstrate that arctigenin exerts anticolitis effect through activating ERβ and down-regulating FAO to prevent GSDMD-N oligomerization and consequent pyroptosis of colonic macrophages. Burdock and its main active ingredient arctigenin merit development as functional foods or therapeutic agents for ulcerative colitis.