Cystathionine beta-synthase alleviates intervertebral disc degeneration by inhibiting ferroptosis of nucleus pulposus cells via the PI3K-AKT Axis

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, affecting 619 million people worldwide in 2020, yet no effective disease-modifying therapy is clinically available to reverse its progression. Ferroptosis has been proven to be a core driver of IVDD by inducing injury to nucleus pulposus cells (NPCs). The regulatory role of cystathionine β-synthase (CBS) in IVDD and its underlying molecular mechanisms remain unclear. This study aimed to investigate the biological function of CBS in IVDD and elucidate the mechanism by which it regulates NPC ferroptosis. We found that CBS expression was significantly downregulated in degenerated human NP tissues and rat IVDD models and was negatively correlated with degeneration severity and ferroptosis activation. Functional assays showed that CBS knockdown markedly exacerbated TBHP-induced matrix metabolic imbalance, senescence, and ferroptosis in NPCs, while CBS overexpression effectively alleviated these pathological phenotypes. Transcriptomic analysis, biochemical validation, and pharmacological inhibition experiments implicated PI3K-AKT signaling in the ferroptosis-related effects associated with CBS modulation in NPCs. In vivo, S-Adenosyl-L-methionine (SAM) administration attenuated needle puncture-induced IVDD in rats, restored disc height and NP water content, and suppressed intradiscal ferroptosis. Because SAM has pleiotropic biological actions, these in vivo effects cannot be attributed exclusively to CBS. Collectively, our findings support a protective role for CBS against IVDD through suppression of NPC ferroptosis and implicate PI3K-AKT signaling as a contributing pathway.