SPARC Drives Tubulointerstitial Fibrosis through Regulating the CBP-DOT1L Pathway.

Renal tubulointerstitial fibrosis (TIF) is a central pathological feature driving the progression of chronic kidney disease (CKD) toward end-stage renal failure. Despite advances in understanding fibrotic mechanisms, effective anti-fibrotic therapies remain limited. Here, we identify SPARC, a matricellular protein expressed in proximal tubular epithelial cells (PTECs), as a key mediator of TIF. SPARC expression strongly correlates with fibrosis severity in both human CKD biopsies and murine models of unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). Genetic ablation of Sparc markedly attenuates renal fibrosis in these models. Mechanistically, SPARC stabilizes DOT1L protein, enhancing H3K79 di-methylation (H3K79me2) and promoting fibrotic changes in PTECs. This process is orchestrated by the acetyltransferase CBP, whose regulation of DOT1L stability depends on MEK-ERK signaling. The SPARC-CBP-DOT1L axis thus defines a previously unrecognized epigenetic pathway driving renal fibrosis. Our findings establish SPARC as a critical driver of TIF and highlight the SPARC-CBP-DOT1L signaling cascade as a promising therapeutic target for halting fibrotic progression in CKD.