Abstract: FR-PO1182
p-Coumaric Acid Ameliorates Inflammation and Fibrosis in Hyperuricemic Nephropathy by Targeting Cathepsin B
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Li, Feng Qin, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, China
- Wang, Yanzhe, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, China
- Wu, Yue, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, China
- Wang, Jialing, Bengbu Medical University, Bengbu, Anhui, China
- Chen, Xinyue, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, China
- Wu, Tong, Bengbu Medical University, Bengbu, Anhui, China
- Wang, Xiaoxia, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, China
Background
Hyperuricemic nephropathy (HN), a prevalent metabolic disorder, is characterized by tubulointerstitial inflammation and fibrosis. Although NLRP3 inflammasome activation plays a pivotal role in HN pathogenesis, effective therapeutic strategies are lacking.
Methods
We screened a series of anti-inflammatory phenolic compounds in uric acid (UA)-stimulated HK-2 cells, and identified p-coumaric acid (p-CA) as a potent lead that significantly inhibited NLRP3 inflammatory pathway. The therapeutic efficacy of p-CA was further validated in HN rat models. Multi-omics analysis, surface plasmon resonance, circular dichroism spectroscopy, and enzymatic activity assays identified Cathepsin B (CTSB) as the molecular target of p-CA. Mechanistic investigations included lysosomal isolation, co-immunoprecipitation, genetic knockdown, and pharmacological inhibition of CTSB. Clinical correlations between CTSB levels and renal function were analyzed in HN patients.
Results
p-CA exhibited robust anti-inflammatory and anti-fibrotic effects in both UA-stimulated HK-2 cells and HN rat models. Mechanistic studies revealed that p-CA directly binds to the lysosomal cysteine protease CTSB, altering its spatial conformation and inhibiting its enzymatic activity. UA-induced lysosomal membrane permeabilization (LMP) triggered CTSB release into the cytosol, where it interacted with NLRP3 to activate the NLRP3-ASC-caspase-1-GSDMD-N-IL-18/IL-1β signaling cascade, driving inflammation and fibrosis. Pharmacological inhibition of CTSB by p-CA or its genetic silencing effectively suppressed this pathway, attenuating disease progression. Clinically, elevated serum and urinary CTSB levels correlated with impaired renal function in HN patients.
Conclusion
Our findings not only highlight p-CA as a novel therapeutic candidate for HN but also identify CTSB as a promising druggable target for this disease.
Funding
- Government Support – Non-U.S.