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Recent studies have identified abnormally elevated levels of the histidine\u2010derived metabolite imidazole propionate (ImP) in the serum of type 2 diabetes mellitus patients. However, the pathophysiological implications of excessive ImP on renal function and its underlying molecular mechanisms remain poorly characterized. This study is the first to elucidate the detrimental effects of ImP on renal function in mice and its molecular mechanisms. Our findings demonstrate that ImP exacerbates renal dysfunction and induces structural and functional abnormalities in renal tubules. Mechanistically, ImP significantly suppresses autophagy in renal tubular epithelial cells and activates the reactive oxygen species (ROS)\u2010NOD\u2010like receptor pyrin domain\u2010containing 3 (NLRP3) signaling pathway, thereby promoting the expression of the pro\u2010inflammatory cytokine interleukin\u20101\u03b2 (IL\u20101\u03b2). Notably, the mechanistic target of rapamycin (mTOR) inhibitor rapamycin (Rap) restores autophagy, inhibits the ROS\/NLRP3\/IL\u20101\u03b2 axis, and mitigates ImP\u2010induced renal injury. Transcriptomic sequencing of mouse kidneys reveals that ImP upregulates the expression of autophagy\u2010 and inflammation\u2010related genes, while its inhibitor suppresses these genetic alterations. This study highlights the potential nephrotoxic effects of ImP and underscores the therapeutic value of Rap, providing a theoretical foundation for understanding the role of gut microbiota metabolites in the pathogenesis, prevention, and treatment of kidney diseases.<\/jats:p>","DOI":"10.1155\/mi\/2457371","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:06:51Z","timestamp":1773029211000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Imidazole Propionate Induces Kidney Damage by Activating the ROS\u2010NLRP3 Signaling Pathway Through mTOR Inhibition of Autophagy in Renal Tubular Epithelial 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