Friedelin Ameliorates Nucleus Pulposus Inflammation by Increasing p65 Autophagic Degradation to Inhibit <scp>NF</scp> ‐ <scp>κB</scp> Signalling Pathway

Intervertebral disc degeneration (IVDD) is a prevalent disorder associated with chronic inflammation, significantly affecting spinal health and general quality of life. This study examines the anti-inflammatory properties of Friedelin (FD) and its impact on the NF-κB signalling pathway in relation to IVDD. In vivo experiments utilising cervical intervertebral disc tissue from mice exhibiting cervical spine instability and in vitro assays with nucleus pulposus (NP) cells revealed that FD treatment significantly diminished NP degeneration and inflammatory cytokine production, concurrently inhibiting NF-κB activation. FD triggered autophagic clearance of p65, reducing inflammatory cytokine output. This effect was mediated by selective inhibition of p65 phosphorylation, independent of IKK activity, highlighting its targeted action on NF-κB signalling. Moreover, FD enhanced the association between p65 and the E3 ubiquitin ligase RNF182, facilitating p65 degradation via autophagy. The findings indicate that FD mitigates IVDD by diminishing NP degradation and inflammation while also presenting a potential therapeutic strategy that targets the NF-κB signalling pathway through autophagic processes.