# Friedelin Ameliorates Nucleus Pulposus Inflammation by Increasing p65 Autophagic Degradation to Inhibit NF‐κB Signalling Pathway

## TL;DR

Friedelin reduces inflammation in spinal discs by boosting autophagy of p65, offering a new treatment approach for disc degeneration.

## Contribution

FD's novel mechanism of inhibiting NF-κB via autophagic p65 degradation is newly identified for IVDD treatment.

## Key findings

- FD reduces NP degeneration and inflammatory cytokines in mice and NP cells.
- FD inhibits NF-κB activation by promoting p65 autophagy without affecting IKK activity.
- FD enhances p65-RNF182 interaction, leading to p65 degradation via autophagy.

## Abstract

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.