Bruceine A attenuates renal tubulointerstitial fibrosis by inhibiting the Wnt7a/PI3K/AKT pathway

Introduction Tubulointerstitial fibrosis (TIF) is a major pathological feature of progressive chronic kidney disease (CKD), yet effective pharmacological therapies remain limited. Bruceine A (BA), a quassinoid isolated from Brucea javanica , has been reported to exert renoprotective effects in glomerular diseases. However, its pharmacological role in renal TIF and the underlying mechanisms remain poorly defined. Methods In this study, we investigated the effects of BA in two classic animal models of TIF, unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI), as well as in TGF-β1-stimulated HK-2 cells. Results BA significantly attenuated renal histopathological injury, inflammatory responses, and fibrotic changes in both in vivo models, and improved renal function in UIRI mice. BA dose-dependently suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibrotic responses in HK-2 cells. Mechanistically, RNA sequencing identified Wnt7a as a BA-responsive gene in fibrotic kidneys. BA consistently reduced Wnt7a expression in vivo and in vitro, while integrated RNA-seq and network pharmacology analyses implicated PI3K/AKT signaling as a key downstream pathway, which was further supported by reduced PI3K and AKT phosphorylation after BA treatment. Moreover, recombinant Wnt7a protein and the AKT agonist SC79 partially reversed BA-mediated suppression of fibrotic marker expression in HK-2 cells. Recombinant Wnt7a also partially restored PI3K/AKT activation. Discussion Collectively, these findings suggest that BA attenuates renal tubulointerstitial injury and fibrosis, potentially through modulation of the Wnt7a/PI3K/AKT signaling pathway, supporting its potential as a therapeutic candidate for TIF.