Abstract: TH-PO0839
Asiaticoside Directly Binds CD40 with Species-Selective Regulation to Attenuate Renal Fibrosis
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Xie, Li-jun, Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
- Liu, Bi-Cheng, Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
Background
Asiaticoside (AS) alleviates renal fibrosis. We previously identified STAT3 as a direct target of AS. This study aimed to identify another target, CD40, and elucidate the multi-target mechanism of AS.
Methods
UUO mice were treated with AS (100 mg/kg/d) for 10 days. Renal fibrosis and macrophage infiltration were assessed by Masson staining, α-SMA and F4/80 immunohistochemistry. Serum cytokines were measured by Luminex. DARTS-LC-MS/MS was used for target identification. CD40/CD40L expression was examined by flow cytometry, qPCR and immunofluorescence. Public scRNA-seq data were analyzed for cellular sources of CD40/CD40L. Downstream signaling was profiled by phosphoproteomic arrays and qPCR. SPR and molecular dynamics simulations characterized binding and species differences.
Results
AS attenuated renal fibrosis, reduced macrophage infiltration, downregulated CXCL1, CCL2, ICAM1 and NFKBIA, and decreased serum IL-6 and TNF-α levels. DARTS-LC-MS/MS identified CD40 as a direct target of AS (ratio 62, p=0.0008). AS downregulated CD40 and CD40L expression in vivo and in vitro. scRNA-seq revealed CD40 on macrophages/DCs and CD40L on Th17/Treg cells, with spatial proximity suggesting macrophage-T cell crosstalk. Phosphoproteomic arrays showed AS inhibited CD40 downstream MAPK/p38/NF-κB signaling. SPR showed moderate binding to human CD40 (KD 330 μM) and stronger binding to murine CD40 (KD 97.1 μM). Molecular dynamics simulations revealed opposite effects: AS stabilized the human CD40/CD40L complex but destabilized the murine counterpart, showing striking species selectivity.
Conclusion
CD40 is another direct target of AS. AS suppresses renal inflammation and fibrosis by targeting CD40 and STAT3, inhibiting MAPK/p38/NF-κB signaling and disrupting macrophage-T cell crosstalk. The species-selective regulation of CD40 by AS provides a cautionary note for CD40-targeted drug development.