β‐Mangostin Attenuates TET2‐Mediated DNA Demethylation of Prkcg in the Prevention of Intervertebral Disc Degeneration

Abstract 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.