Low back pain, predominantly linked to intervertebral disc (IVD) degeneration, represents a significant global health challenge. Our research demonstrates that nucleus pulposus (NP) cells activate the integrated stress response (ISR) during disc degeneration, as revealed by transcriptomic analysis of human samples. Using a transgenic mouse model with a Col10a1 13-bp deletion (13del), we observed triggered ISR in the NP, characterized by ATF4 and ATF5 expression, SOX9 upregulation, and premature fibrosis-related gene expression. Early intervention with ISRIB, an ISR inhibitor, successfully mitigated these abnormalities. Through inducible label-retaining studies, we identified cycling cells primarily in the peripheral NP region. The 13del mutation depleted these cycling cells early and increased susceptibility to mechanical damage. Our findings emphasize the crucial roles of endplate structure and NP progenitors in disc health, while highlighting ISR inhibition and cycling cell preservation as potential therapeutic strategies for intervertebral disc degeneration.