NF-κB signaling in osteoarthritis: integrating mechanical stress, innate immunity, and cartilage degeneration.
- 2026-06-05
- Frontiers in immunology 17
- Peng Wan
- Yimin Zheng
- PubMed: 42327716
- DOI: 10.3389/fimmu.2026.1842443
Study Design
- Type
- Review
Osteoarthritis (OA) is a complex and multifactorial joint disease that was traditionally regarded as a consequence of mechanical wear and tear, but is now increasingly recognized as a disorder driven by chronic low-grade inflammation and dysregulated stress responses. Nuclear factor-κB (NF-κB) has emerged as a pivotal regulator in OA; however, its role extends well beyond that of a linear inflammatory pathway. In this review, we synthesize recent evidence supporting NF-κB as an important integrative signaling node through which mechanical stress, innate immune activation, and metabolic cues converge to influence joint degeneration. We discuss how mechanotransduction mediated by ion channels, mitochondrial dysfunction-associated DNA sensing, and danger-associated molecular patterns converge on NF-κB activation, thereby establishing feed-forward inflammatory circuits. Downstream, NF-κB-associated signaling is closely involved in extracellular matrix degradation, chondrocyte fate decisions-including senescence, apoptosis, and ferroptosis-synovial inflammation and fibrosis, immune microenvironment remodeling, and subchondral bone alterations. Importantly, the biological consequences of NF-κB signaling are highly context dependent and are shaped by the source, intensity, and duration of upstream stimuli, as well as by the metabolic and aging status of joint cells. Finally, we summarize emerging therapeutic strategies targeting NF-κB-associated networks at multiple hierarchical levels and highlight the importance of mechanism-based patient stratification and rational combination therapies. By positioning NF-κB as a hub of signaling integration, this review provides a unifying framework for understanding OA pathogenesis and suggests new directions for precision interventions aimed at restoring joint homeostasis.