FGF21-Mediated Upregulation of SIRT1 Delays Intervertebral Disc Degeneration by Promoting PINK1/Parkin Dependent Mitophagy Through Deacetylation of FOXO3.

Bioinformatic analysis identified FGF21 as a key gene regulating nucleus pulposus cell senescence in intervertebral disc degeneration.

• FGF21 was identified through bioinformatic analysis as a central regulator of NPC senescence.
• FGF21 expression was significantly downregulated in both human and rat degenerated intervertebral discs.
• Downregulation of FGF21 was closely associated with upregulation of senescence markers P16, P21, and P53.
• FGF21 expression correlated with clinical pathological features including age, symptom duration, and Pfirrmann grading.

FGF21 intervention significantly alleviated tert-butyl hydroperoxide (TBHP)-induced nucleus pulposus cell senescence and mitochondrial damage in vitro.

• TBHP was used as the in vitro oxidative stress model to induce NPC senescence and mitochondrial damage.
• FGF21 treatment significantly reduced senescence markers induced by TBHP.
• FGF21 intervention attenuated mitochondrial damage in NPCs under oxidative stress conditions.

FGF21 upregulated SIRT1 and promoted deacetylation of FOXO3 at specific lysine sites to enhance mitophagy.

• FGF21 mechanistically upregulated SIRT1 expression in NPCs.
• SIRT1-mediated deacetylation of FOXO3 occurred specifically at lysine sites K241, K258, K289, and K568.
• Deacetylation of FOXO3 at these sites enhanced mitophagy in NPCs.
• Enhanced mitophagy was dependent on the PINK1/Parkin pathway.

FGF21 treatment significantly improved disc height and histological scores in a rat intervertebral disc degeneration model in vivo.

• In vivo experiments used a rat IDD model to assess FGF21 therapeutic effects.
• FGF21 treatment significantly improved disc height index in treated rats compared to controls.
• Histological scores were significantly improved following FGF21 treatment.
• SIRT1 knockdown attenuated the protective effects of FGF21 on disc height and histological scores, confirming SIRT1 dependency.

SIRT1 knockdown attenuated the protective effects of FGF21 in vivo, confirming that FGF21's beneficial effects are mediated through the SIRT1/FOXO3/PINK1/Parkin axis.

• SIRT1 knockdown experiments were performed in the rat IDD model alongside FGF21 treatment.
• Knockdown of SIRT1 reversed the improvements in disc height conferred by FGF21.
• Histological scores were similarly attenuated by SIRT1 knockdown in FGF21-treated animals.
• These results identified the FGF21-SIRT1/FOXO3/PINK1/Parkin axis as a promising therapeutic target for IDD.

NPC senescence is identified as a central mechanism driving the pathological progression of intervertebral disc degeneration.

• IDD is described as a common degenerative spinal disease and a leading cause of low back pain and disability.
• Senescence of nucleus pulposus cells is characterized as central to IDD pathological progression.
• The regulatory mechanisms of NPC senescence in IDD were previously unclear prior to this study.
• Senescence markers P16, P21, and P53 were used to characterize NPC senescence in both human and rat tissues.