BACKGROUND: p-coumaric acid (p-CA), a hydroxycinnamic acid derivative, is recognized for its antioxidant and anti-inflammatory properties
however, its pharmacological effects on renal fibrosis remain insufficiently explored. PURPOSE: This study aimed to evaluate the therapeutic potential of p-CA in renal fibrosis and elucidate its underlying mechanisms through extensive molecular and cellular analyses. METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS) was employed to analyze metabolic alterations associated with renal fibrosis induced by unilateral ureteral obstruction (UUO). Immune cell dynamics were assessed using cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq). Further validation was performed using flow cytometry, Western blot (WB), quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and immunofluorescence (IF) to evaluate the renoprotective effects of p-CA at the cellular and molecular levels. RESULTS: p-CA levels were significantly reduced in fibrotic renal tissues. Administration of exogenous p-CA restored renal function, alleviated tissue damage, and inhibited G2/M cell cycle arrest and epithelial-mesenchymal transition (EMT) in tubular epithelial cells (TECs). CyTOF and scRNA-seq analyses revealed that p-CA treatment decreased M2 macrophage proliferation, intercellular communication, and differentiation in fibrotic kidney tissues, resulting in reduced renal fibrosis. Additional experimental validations confirmed that p-CA specifically targeted M2 macrophages, suppressing their contribution to fibrotic progression. CONCLUSIONS: p-CA exerts renoprotective effects by targeting M2 macrophages, disrupting their interaction with TECs, and attenuating fibrotic progression. These findings underscore the potential of p-CA as a novel therapeutic approach for renal fibrosis.