Huaier-derived neutral polysaccharide WHPB mitigates renal fibrosis via CSF-1R/PI3K/AKT-mediated FUT8 inhibition.

Abstract

BACKGROUND: Renal interstitial fibrosis (RIF) is a hallmark of chronic kidney disease (CKD). Fucosyltransferase 8 (FUT8), which mediates core fucosylation (CF), plays a central role in promoting RIF, though its therapeutic potential remains incompletely explored. Huaier, a traditional Chinese medicine widely used in the clinical treatment of various tumors, has demonstrated promising potential in mitigating renal injury, highlighting its potential as a treatment to suppress FUT8 expression. OBJECTIVE: This study aimed to evaluate Huaier extract (HET) and its polysaccharide WHPB against RIF, identify WHPB's targets, and elucidate its mechanisms involving FUT8 regulation. METHODS: Three murine models of renal interstitial fibrosis (RIF) induced by folic acid, adenine, and unilateral ureteral obstruction (UUO) were established to evaluate the anti-fibrotic efficacy of HET and WHPB. The structure of WHPB was characterized using nuclear magnetic resonance (NMR) spectroscopy. Proteomic analysis was employed to identify differentially expressed proteins and potential targets of WHPB. Surface plasmon resonance (SPR) was applied to confirm binding interactions between WHPB and candidate receptors. Functional assays in macrophages and renal tubular epithelial cells (RTECs) were conducted to evaluate the effects of WHPB on FUT8 expression and associated signaling pathways. RESULTS: WHPB selectively bound to CSF-1R on macrophages and injured RTECs, inhibiting the CSF-1R/PI3K/AKT/CREB-1/STAT3 pathway and downregulating FUT8. This reduced core fucosylation of fibrosis-related receptors. WHPB attenuated fibrosis in all models and accumulated preferentially in diseased kidneys. CONCLUSION: WHPB targets CSF-1R to suppress FUT8 via PI3K/AKT signaling, blocking key fibrotic pathways. These findings support WHPB's development as a targeted therapy that suppresses FUT8 for RIF.