Deletion of Circadian Rhythms Gene BMAL1 Impairs the Intestinal Epithelial Barrier and Exacerbates Intestinal Inflammation by Inducing Pyroptosis.

The circadian clock plays a crucial role in the pathogenesis of various inflammatory and autoimmune diseases, including ulcerative colitis (UC). Deletion of the core transcription factor BMAL1 exacerbated the severity of colitis. However, the underlying molecular mechanisms of BMAL1 in UC remain unclear. We found that BMAL1 was downregulated in UC tissues and in LPS-induced MODE-K cells, whereas CXCL1 was highly expressed. Overexpression of BMAL1 reduced LPS-induced pyroptosis in MODE-K cells and restoring the expression of ZO-1, Claudin-1, and Occludin, thereby improving intestinal epithelial barrier function. Mechanistically, BMAL1 can negatively regulate the CXCL1 expression by inhibiting the activity of its promoter. Additionally, proteomics analysis identified MEF2A as a downstream protein of BMAL1. The protective effect of BMAL1 on MODE-K cells was achieved through direct negative regulation of CXCL1 or indirect negative regulation of MEF2A expression. Thus, BMAL1 plays a protective role in maintaining the integrity of the intestinal epithelial barrier and represents a potential therapeutic target for UC treatment.