Intervertebral disc degeneration (IDD) induced lower back pain is a main cause of disability, resulting in a substantial workforce loss worldwide and placing a substantial burden on the global economy and healthcare systems. However, no effective disease-modifying therapies presently exist for IDD or its related pathologies. Single-cell sequencing analyses reveal progressive M1 macrophage polarization in NP cells correlating with IDD severity, underscoring the therapeutic imperative for dual-targeting agents addressing both inflammatory dysregulation and matrix homeostasis. β-mangostin (β_Man) is screened to be proven to possess potential therapeutic effects in alleviating IDD. β_Man possesses anti-inflammatory capabilities, which include remodeling the homeostasis of the extracellular matrix, regulating macrophage polarization, and inhibiting apoptosis in the nucleus pulposus. TET2-Prkcg exerts significant regulatory functions downstream of β_Man. Mechanically, β_Man mediated reduction of TET2 maintains the DNA methylation of Prkcg rather than hydroxymethylation, which promotes mitophagy and alleviates the inflammatory microenvironment. β_Man represents a promising novel therapeutic strategy for IDD treatment. The TET2-Prkcg axis emerges as a novel therapeutic target for IDD treatment.