Background: The incidence of intervertebral disc degeneration (IVDD) is a common degenerative disease with infiammation, decreased autophagy, and progression of fibrosis as its possible pathogenesis. Physalin A (PA) is a widely studied anti-infiammatory drug. However, its therapeutic effects on IVDD remain unexplored. Therefore, we aimed to explore the therapeutic potential of PA in IVDD progression.Materials and methods: In vivo, we investigated PA bioactivity using a puncture-induced IVDD rat model. IVDD signals and height changes were detected using X-ray, micro-CT, and MRI, and structural and molecular lesions using histological staining and immunohistochemistry of intervertebral disc sections. In vivo, interleukin-1 beta (IL-1 beta) and TGF-beta 1 were employed to establish infiammation fibrotic nucleus pulposus (NP) cells. The PA effect duration, concentration, infiuence pathways, and pathological changes in IVDD treatment were elucidated using western blotting, real-time PCR, and immunofiuorescence.Results: PA exerted significant effects on IVDD remission due to anti-infiammation, fibrosis reduction, and autophagy enhancement. In vitro, PA improved infiammation by blocking the NF-Kappa B and MAPK pathways, whereas it promoted autophagy via the PI3K/AKT/mTOR pathway and affected fibrotic progression by regulating the SMAD2/3 pathway. Moreover, PA improved the disc degeneration process in IVDD model.Conclusions: PA exhibited significant anti-infiammatory and anti-fibrotic effects and improved autophagy in vivo and in vitro IVDD models, thus effectively relieving IVDD progression, indicating it is a promising agent for IVDD treatment. The translational potential of this article: This study successfully reveals that PA, a natural bioactive withanolide, effectively relieved IVDD progression via infiammation inhibition, fibrosis reduction, and autophagy enhance-ment, indicating it is a promising agent for IVDD treatment.