Indole‐3‐Carboxaldehyde Inhibits Inflammatory Response and Lipid Accumulation in Macrophages Through the <scp>miR</scp>‐1271‐5p/<scp>HDAC9</scp> Pathway

Indole-3-carboxaldehyde (ICA), a microbiota-derived tryptophan metabolite, has been reported to protect against atherosclerosis. However, the molecular mechanisms for its atheroprotective effect remain largely unknown. This study aimed to explore the influence of ICA on lipid accumulation and inflammatory response in THP-1 macrophage-derived foam cells. Our results showed that administration of ICA upregulated the expression of miR-1271-5p, ATP binding cassette transporter A1 (ABCA1) and ABCG1, downregulated histone deacetylase 9 (HDAC9) expression and inhibited macrophage lipid accumulation. ICA treatment also facilitated macrophage polarisation to the M2 phenotype and alleviated inflammatory response, as evidenced by decreased IL-6 levels and increased IL-10 levels. HDAC9 was identified as a direct target of miR-1271-5p. HDAC9 overexpression or miR-1271-5p knockdown decreased the effect of ICA on ABCA1 and ABCG1 expression as well as inflammatory response. Taken together, these results suggest that ICA can suppress lipid accumulation and mitigate inflammatory response in macrophages by activating the miR-1271-5p/HDAC9 signalling cascade, thereby providing new explanations for how ICA reduces atherosclerosis.