Abstract

Genome-wide association studies have implicated proline/serine-rich coiled-coil 1 ( PSRC1 ) in coronary artery disease (CAD) pathogenesis. Our previous studies demonstrated that Psrc1 deficiency accelerates atherosclerosis via gut microbial dysbiosis, characterized by a substantial depletion of Akkermansia muciniphila . Recent studies implicate microbiome-dependent tryptophan metabolism as a novel checkpoint in atherosclerosis, with specific microbial taxa regulating metabolite-driven immune responses. The mechanism by which Psrc1 modulates atherosclerosis through A. muciniphila and its regulation of tryptophan metabolism remains unclear. Here Psrc1 knockout mice exhibited reduced colonic mucin content, altered tryptophan metabolic enzyme expression and diminished levels of Trp metabolites including indoleacetic acid (IAA), with concomitant suppression of Ahr signaling in macrophages. In vivo analysis revealed that Psrc1 knockout diminishes Ahr through A. muciniphila -dependent IAA depletion. In vitro experiments further uncovered that Psrc1 stabilizes Ahr protein via ubiquitin carboxyl terminal hydrolase L3 (Uchl3)-mediated deubiquitylation. In addition, we identified plasma IAA levels positively correlating with decreased PSRC1 expression in peripheral blood mononuclear cells from patients with CAD. Furthermore, therapeutic restoration of a live A. muciniphila– IAA axis through oral supplementation reversed atherosclerosis in Psrc1 knockout mice. Notably, oral IAA supplementation substantially ameliorated atherosclerosis in Psrc1 knockout mice by suppressing plaque macrophage apoptosis. Crucially, co-administration of the Ahr antagonist CH-223191 abolished these benefits, confirming Ahr dependence. Our findings position PSRC1 as a critical regulator of the A. muciniphila– IAA–Ahr axis and nominate microbiome-targeted Ahr activation as a precision therapeutic strategy for patients with CAD with PSRC1 loss-of-function variants.