YY1-VDR axis-mediated autophagy slows the progression of intervertebral disc degeneration

Background: Aging is accompanied by degeneration of the intervertebral discs (IVDD), which leads to a poor quality of life and a significant socioeconomic burden. The present study aimed to explore the effect of transcription factor Yin and Yang 1 (YY1) on IVDD and to elucidate the potential underlying mechanism.

Methods: Differentially expressed genes in nucleus pulposus (NP) tissues from patients with early or advanced IVDD were screened out using transcriptome Sequencing. Mice were subjected to IVDD modeling, and NP cells were treated with H₂O₂ and lentivirus. The oxidative stress and Autophagy were assessed in mice and H₂O₂-treated NP cells. Genes closely associated with YY1 expression were predicted, and ChIP and dual-luciferase experiments were conducted to authenticate their binding relationship. Autophagy agonist rapamycin rescue experiments were designed in vitro. Finally, the upstream mechanism for YY1 downregulation was examined.

Results: YYI expression was reduced in NP tissues of patients with advanced IVDD, and mice overexpressing YY1 showed significantly decreased oxidative stress and Apoptosis, and increased levels of autophagy-related proteins. Overexpression of YY1 reduced the Apoptosis and ROS levels, decreased the expression of Apoptosis markers, and increased the Autophagy in H₂O₂-treated NP cells. YY1 bound to the vitamin D3 receptor (VDR) promoter and stimulated the VDR transcription. Rapamycin-treated NP cells showed increased expression of LC3, decreased ROS levels, and Apoptosis. YY1 methylation increased with worsening IVDD.

Conclusions: Activation of the VDR by YY1 improves oxidative stress and reduces NP cell Apoptosis by promoting Autophagy. This process may serve as a promising therapeutic target for managing IVDD.

Autophagy; Intervertebral disc degeneration; Oxidative stress; VDR; YY1.