Modern pharmacological evaluation of standardized naringin-rich Citrus maxima peel fractions for osteoarthritis through the NF-κB/COX-2/MMP-13 network

Abstract

Background Osteoarthritis (OA) is characterized by chronic inflammation and progressive cartilage degradation driven by activation of the NF-κB/MMP-13/COX-2 signaling axis. Citrus maxima ( syn. Citrus grandis) is represented in traditional Chinese medicine by Huajuhong (Citri Grandis Exocarpium), a citrus-derived medicinal material traditionally used for respiratory and phlegm-related disorders. However, the pharmacological potential of chemically standardized, naringin-rich pomelo fractions for osteoarthritis remains insufficiently characterized. This study therefore investigated whether chemical enrichment of naringin translates into enhanced multi-target chondroprotective activity. Methods Pomelo peel was extracted, chemically standardized, and fractionated into a crude pomelo peel extract (PPE), naringin-enriched fraction (NEF), and naringin-depleted fraction (NDF). Phytochemical composition was characterized using HPLC-DAD and untargeted metabolomics. Major metabolites were evaluated by molecular docking against IKKβ, COX-2, MMP-13, and p38 MAPK. Chondroprotective activity was validated in IL-1β-stimulated human C28/I2 chondrocytes by assessing cell viability, inflammatory and anabolic gene expression, cytokine secretion, NF-κB nuclear translocation, oxidative stress, extracellular matrix preservation, apoptosis, and mitochondrial membrane potential. Results The extraction procedure yielded a reproducible naringin-rich extract, while metabolomic profiling identified flavanone glycosides as the dominant phytochemical class. Molecular docking predicted favorable binding of naringin to all four osteoarthritis-associated targets. In vitro, the NEF and high-dose PPE significantly suppressed NF-κB activation and reduced RELA, PTGS2, MMP13, ADAMTS5, NOS2, IL6, PGE₂, TNF-α, and MMP-13 while preserving COL2A1, ACAN, and SOX9 expression. Treatment also reduced intracellular reactive oxygen species, nitric oxide production, extracellular matrix degradation, and apoptosis, while maintaining mitochondrial membrane potential and proteoglycan content. Overall, the NEF demonstrated greater biological activity than the naringin-depleted fraction, supporting naringin as a major contributor to the observed activity. Conclusions Naringin-rich pomelo peel preparations attenuated IL-1β-induced inflammatory, catabolic, oxidative, and mitochondrial alterations in C28/I2 chondrocytes through coordinated modulation of the NF-κB/COX-2/MMP-13 network. These findings support further preclinical investigation of standardized pomelo peel preparations as sustainable sources of chondroprotective phytochemicals. These findings establish a composition–activity relationship linking naringin enrichment to multi-target chondroprotection and support the modern pharmacological development of standardized Citrus maxima -derived preparations for further preclinical investigation in osteoarthritis.

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