Modulation of inflammatory signaling pathways by natural products in osteoarthritis: Mechanisms, challenges, and future directions

Osteoarthritis (OA) is a degenerative joint disease that is characterized by dysregulated inflammatory signaling that disrupts cartilage homeostasis and presents a significant therapeutic challenge. Although current treatments primarily focus on symptom management, this review explores the growing interest in anti-inflammatory natural products as potential disease-modifying therapies. This review aims to: identify key inflammatory pathways as promising drug targets, summarize recent findings on natural products that modulate these pathways, and discuss challenges and future directions. A comprehensive literature search was conducted using databases such as PubMed and Web of Science, focusing on studies published in the last decade. Central to OA pathogenesis is persistent inflammation resulting from cytokine /chemokine-driven catabolic signaling, which is exacerbated by the overactivation of NF kappa B, MAPK, and PI3K/AKT pathways. Numerous plant-derived compounds exert inhibitory effects on these inflammatory cascades through mechanisms including NF-kappa B nuclear translocation suppression, MAPK phosphorylation blockade, and modulation of PI3K/AKT activity. However, clinical translation faces several complexities, such as bioavailability, precise targeting, and disease heterogeneity. Addressing these challenges using advanced technologies could enable the development of natural product-based OA therapeutics. Innovative research strategies are needed to fully leverage the therapeutic potential of these compounds in the management of OA.