Citropten from Citrus sinensis peel protects against obstructive chronic kidney disease: insights from network pharmacology and experimental validation

Abstract

Chronic kidney disease (CKD) is a global health challenge affecting millions, yet effective therapeutic options remain scarce. This study explores the renoprotective potential of citropten (CTP), a citrus-derived coumarin derivative isolated from the peel of Citrus sinensis, using an integrated in silico and in vivo strategy. Pharmacokinetic screening indicated that CTP possesses favourable drug-likeness, oral bioavailability, and a safety profile. Network pharmacology identified 188 CTP-associated CKD targets, generating a robust interaction network with an average node degree of 12, from which 13 hub targets were identified. Pathway enrichment analyses showed that these targets are predominantly involved in inflammatory, mitophagy, and fibrotic signalling pathways. Transcriptomic validation showed that 9 of 13 hub targets were dysregulated in CKD, reinforcing their clinical relevance. Molecular docking suggested strong interactions between CTP and key regulatory proteins, particularly MAPK14, NFE2L2, and PARP1. These computational findings were experimentally validated in a unilateral ureteral obstruction (UUO) rat model of CKD. Oral administration of CTP (10 and 20 mg kg⁻¹ day⁻¹ for 21 days) significantly preserved kidney function and histological architecture. CTP treatment also significantly attenuated extracellular matrix (ECM) accumulation and epithelial–mesenchymal transition (EMT), indicating reduced renal fibrosis. Mechanistic evaluation of hub targets demonstrated that CTP effectively modulated the Nrf2/NF-κB1/PARP1 signalling axis, a pivotal regulator of oxidative stress and inflammation. Consistent with pathway prediction, downstream validation revealed that CTP activated PINK1/Parkin/LC3B-mediated mitophagy, thereby restoring mitochondrial quality. Collectively, these findings suggest that CTP is a promising food-derived, multi-target bioactive candidate with potential therapeutic relevance for CKD management.