PHGDH‐Mediated Serine Metabolism in Nucleus Pulposus Cells Is a Potential Therapeutic Target for Intervertebral Disc Degeneration

ABSTRACT

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, driven largely by nucleus pulposus cell (NPC) senescence under chronic hypoxia and nutrient stress. Serine metabolism regulates senescence, but its role in IVDD remains unclear. Here, transcriptomic profiling reveals that the glycine–serine–threonine pathway is downregulated in senescent NPCs, with marked reduction of the serine synthesis rate limiting enzyme PHGDH. This is confirmed by single cell RNA sequencing of human discs, aged rat tissues, and degenerated human samples, accompanied by decreased intracellular serine. PHGDH silencing or serine deprivation inhibits NPC proliferation, induces senescence, and suppresses matrix anabolism. Mechanistically, PHGDH deficiency lowers α ketoglutarate, impairing histone demethylation and increasing H3K27me3 occupancy at the Rap1b promoter, which silences Rap1b and activates mTORC1, thereby blocking autophagic flux. Additionally, serine starvation depletes glutathione, elevates ROS, and promotes apoptosis. In vivo, AAV mediated PHGDH overexpression alleviates puncture induced IVDD, while a serine deficient diet exacerbates degeneration. Collectively, we uncover a PHGDH/Rap1b/mTORC1/autophagy cascade linking serine deprivation to NPC senescence, and propose that restoring PHGDH or serine availability may be a viable strategy to combat age related disc degeneration.