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Intervertebral disc degeneration (IDD) is a chronic progressive condition mainly caused by excessive inflammatory cytokines. Berberine (BBR) exerts anti-inflammatory effect on diseases and protective effect against IDD. However, the mechanism is not uncertain. This study is aimed at investigating the molecular mechanism of BBR on IDD. Nucleus pulposus (NP) cells were treated with BBR at different concentrations. The IDD rat model was established by acupuncture. The effect of BBR on interleukin- (IL-) 1 β -induced cell proliferation was measured by CCK-8 assay and BrdU staining. The role of BBR in IL-1 β -induced apoptosis, autophagy repression, and extracellular matrix (ECM) degradation was measured by Annexin/PI staining, immunofluorescence, and immunoblot. The effect of BBR on IDD was investigated in rat. Our findings showed that BBR restored cell growth and attenuated apoptosis in IL-1 β -induced NP cells. BBR also prevented the IL-1 β -induced ECM degradation through regulating ECM-related enzymes and factors. Additionally, BBR significantly activated autophagy repressed by IL-1 β . Autophagy stimulated by BBR was diminished by the inhibition of the AMPK/mTOR/Ulk1 signaling pathway. In vivo study also showed BBR attenuated intervertebral disc degeneration. BBR could attenuate NP cells apoptosis and ECM degradation induced by IL-1 β through autophagy by the AMPK/mTOR/Ulk1 pathway. This study suggests BBR might function as an AMPK activator to alleviate IDD progression., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Liaoyuan Huang et al.)