<scp>FGF21</scp> ‐Mediated Upregulation of <scp>SIRT1</scp> Delays Intervertebral Disc Degeneration by Promoting <scp>PINK1</scp> /Parkin Dependent Mitophagy Through Deacetylation of <scp>FOXO3</scp>

Intervertebral Disc Degeneration (IDD) is a common degenerative spinal disease and a leading cause of low back pain and disability. The senescence of nucleus pulposus cells (NPCs) is a central mechanism driving the pathological progression of IDD, though its regulatory mechanisms remain unclear. Bioinformatic analysis identified FGF21 as a key gene regulating NPCs senescence. In both human and rat degenerated intervertebral discs, FGF21 expression was significantly downregulated and closely associated with the upregulation of senescence markers (P16, P21, and P53) and clinical pathological features (age, symptom duration, and Pfirrmann grading). In vitro experiments demonstrated that FGF21 intervention significantly alleviated tert-butyl hydroperoxide (TBHP)-induced NPCs senescence and mitochondrial damage. Mechanistically, FGF21 upregulated SIRT1 and promoted the deacetylation of FOXO3 at lysine sites K241, K258, K289, and K568, thereby enhancing mitophagy and inhibiting NPCs senescence. In vivo, FGF21 treatment significantly improved disc height and histological scores in a rat IDD model, whereas SIRT1 knockdown attenuated these protective effects. In summary, FGF21 inhibits NPCs senescence and delays IDD progression by activating SIRT1-mediated FOXO3 deacetylation and enhancing PINK1-Parkin pathway-dependent mitophagy. Therefore, the FGF21-targeted SIRT1/FOXO3/PINK1/Parkin axis may represent a promising new therapeutic strategy for IDD.