ABSTRACTObjectiveIntervertebral disc degeneration (IVDD) has been closely associated with ferroptosis in nucleus pulposus cells (NPCs), the underlying regulatory mechanisms and therapeutic strategies remain poorly defined. This study aims to delineate how ginsenoside Rg3 mitigates IVDD progression through ferroptosis suppression, providing a basis for clinical translation.MethodAn erastin‐induced nucleus pulposus cell ferroptosis model was established. Suitable Erastin concentrations (0–20 μM) were screened via CCK‐8, qRT‐PCR, and Western blotting based on viability, extracellular matrix (COL2A1/ACAN/ADAMTS5/MMP3) and ferroptosis markers (GPX4/FTH‐1/ACSL4), followed by determination of optimal Rg3 concentrations (0–150 μM) using identical methods. Key targets of Rg3 were predicted through network pharmacology and verified by qRT‐PCR and Western blotting. After establishing a rat tail puncture‐induced IVDD model, local injection of Rg3 was administered. Therapeutic efficacy was evaluated by MRI assessment of nucleus pulposus status and disc height, alongside histological and immunohistochemical analyses of Rg3's role in delaying disc degeneration.Result5 μM Erastin effectively induced ferroptosis in nucleus pulposus cells, reducing cell viability, suppressing expression of extracellular matrix anabolic proteins (COL2A1, ACAN), while promoting catabolic factors (MMP3, ADAMTS5) and downregulating ferroptosis inhibitors (GPX4, FTH‐1). These alterations were significantly reversed by 100 μM Rg3. Integrated network pharmacology and molecular biological validation identified PRKAA2 as the key target mediating Rg3's anti‐degenerative effects. In vivo rat experiments demonstrated that Rg3 treatment preserved disc height and attenuated disc degeneration, with histological and immunohistochemical analyses further confirming its therapeutic efficacy and PRKAA2‐targeted regulation.ConclusionThis study elucidates the therapeutic mechanism of Rg3 in delaying IVDD progression via PRKAA2‐mediated ferroptosis inhibition, providing substantial experimental evidence for its clinical translation as a potential disease‐modifying agent.