Oxidative stress promotes intervertebral disc degeneration through NAT10-mediated IKKβ N4-acetylcytidine modification.

Oxidative stress is a significant risk factor in inducing intervertebral disc degeneration (IDD), yet its precise regulatory mechanism remains unknown. This study aimed to elucidate the role of NAT10-mediated N4-acetylcytidine modification in oxidative stress-induced IDD. Initially, human nucleus pulposus cells (hNPCs) subjected to hydrogen peroxide (H2O2) were examined to clarify how oxidative stress influences cell degeneration via NAT10. Subsequently, animal models were employed to validate the ameliorative impact of modulating NAT10 expression in vivo on IDD. Ultimately, a suite of techniques including acRIP-qPCR and luciferase assays were utilized to investigate the functional mechanisms by which NAT10-mediated N4-acetylcytidine modification regulates IKKβ expression, thereby activating the NF-κB signaling pathway. The expression of NAT10 significantly increased in hNPCs under H2O2 and in severely degenerated nucleus pulposus tissue. Functionally, NAT10 mediated N4-acetylcytidine modification to enhance the expression of IKKβ. This upregulation of IKKβ expression led to the release of IκB's inhibition on P65, thereby activating the NF-κB pathway, which resulted in increased apoptosis of hNPCs, enhanced degradation of the extracellular matrix, and macroscopically promoted IDD. Additionally, inhibiting NAT10 expression both in vitro and in vivo can significantly increase the nucleus pulposus's resistance to oxidative stress, thereby mitigating IDD. Under oxidative stress stimulation, NAT10 upregulated IKKβ expression through N4-acetylcytidine modification, thereby activating the NF-κB signaling pathway to promote IDD, providing a new approach for the treatment of IDD.