Abstract

Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), ultimately leading to end‐stage renal failure. Cytokine receptor‐like factor 1 (CRLF1) is a secreted protein with low or undetectable expression in normal physiology, but it is transcriptionally and translationally upregulated under pathological conditions. In this study, we found CRLF1 to be upregulated in the kidneys of patients with ATN and CKD, positively correlated with renal interstitial fibrosis, and negatively correlated with renal function. In vivo functional inhibition studies demonstrated that CRLF1 suppression significantly improved renal function, mitigated pathological damage, and delayed fibrosis progression in mouse models of IRI or UUO. Further in vitro studies revealed that CRLF1 promotes fibrosis and inflammation in renal tubular epithelial cells (TECs). Mechanistically, we employed chromatin immunoprecipitation (ChIP) to validate SMAD3 binding to the CRLF1 promoter and its transcriptional regulation, while elevated CRLF1 interacts with the VWFA domain of integrin β1 (ITGB1). Furthermore, transcriptomic sequencing revealed that CRLF1 activates the PI3K/AKT signaling pathway, promoting tubular epithelial cell fibrosis progression via ITGB1. These findings underscore the critical role of CRLF1 in renal fibrosis progression and suggest its potential as a therapeutic target for inhibiting the progression from AKI to CKD. During renal fibrosis, SMAD3 acts as a transcription factor for CRLF1, promoting its expression and secretion. CRLF1 then binds to ITGB1 via an autocrine mechanism, activating the PI3K‐AKT signaling pathway to mediate renal fibrosis. This accelerates the progression from AKI to CKD, highlighting the therapeutic potential of targeting CRLF1 for alleviating renal fibrosis.