A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis. Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced FAO and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of renal fibrosis.