Abstract

Highlights What are the main findings? BPIFA2 expression is elevated in renal tubules of CKD patients and correlates with tubulointerstitial fibrosis severity. BPIFA2 facilitates renal interstitial fibrosis by triggering tubular epithelial-mesenchymal transition and macrophage-to-myofibroblast transition. What are the implications of the main findings? BPIFA2 acts as a novel profibrotic mediator and potential therapeutic target against chronic kidney disease. Abstract Tubulointerstitial fibrosis (TIF) represents the final common pathway leading to end-stage renal disease (ESRD) in chronic kidney disease (CKD). Despite fibrosis being well established as a key pathological hallmark, the molecular mediators that drive this process remain incompletely understood. BPI fold-containing family A member 2 (BPIFA2), a secreted innate immune protein of the sPLUNC family, was upregulated in renal tubular epithelial cells across diverse CKD etiologies and strongly correlated with collagen I accumulation and TIF severity. Tubule-specific knockdown of BPIFA2 significantly alleviated renal histopathological injury and fibrosis, whereas exogenous BPIFA2 administration aggravated fibrotic progression. Mechanistically, BPIFA2 promoted epithelial–mesenchymal transition (EMT) in tubular epithelial cells and triggered macrophage-to-myofibroblast transition (MMT) associated with the TGF-β/Smad3 signaling pathway. In conclusion, our findings identify BPIFA2 as a novel profibrotic mediator in CKD. Targeting BPIFA2 or its downstream signaling may offer new therapeutic opportunities for chronic kidney disease.