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Apoptosis and extracellular matrix degradation of the nucleus pulposus are the main initiators of intervertebral disc degeneration (IVDD) and can be explained by endoplasmic reticulum (ER) stress. Thus, pharmacological therapy aimed at suppressing this pathway may be a promising approach for the management of intervertebral disc degeneration. In this study, we aimed to explore the protective effects of Sal003 against intervertebral disc degeneration and its underlying mechanisms. Thapsigargin (Tg)-stimulated rat nucleus pulposus cells and a needle puncture-induced intervertebral disc degeneration rat model were used to explore the protective effects of Sal003. Our results showed that Sal003 inhibited apoptosis and extracellular matrix degradation by suppressing the endoplasmic reticulum stress pathway. The therapeutic effects of Sal003 were also observed in the intervertebral disc degeneration rat model, as evidenced by improved degeneration along with decreased apoptosis and extracellular matrix degradation in intervertebral discs. Our results demonstrated Sal003 as a potential treatment for intervertebral disc degeneration.