Background Intervertebral disk degeneration (IDD) is a common orthopedic disorder, and nucleus pulposus cells (NPCs) serve to stabilize the intervertebral disk. Objective This study was implemented to explore the protective eff ect of endplate stem cells (EPSCs) on IDD. NPCs and EPSCs were isolated from rats and tert -Butyl peroxide (TBHP) was used to treat NPCs and simulate IDD. EPSC-derived conditioned medium (CM) was collected and mixed with a culture medium at diff erent proportions, which was then used to treat NPCs. SOD assay was employed to examine the oxidative stress level in the NPCs. To assess apoptosis and caspase-3 activity, fl ow cytometry and western blots for cleaved PARP1 and BAX were carried out. The mRNA expression levels of diff erent genes were detected by quantitative real-time polymerase chain reaction. Furthermore, the concentrations of amphiregulin (Areg) and infl ammatory factors were measured with ELISA kits and cell signaling pathways were evaluated using western blotting. Results Following TBHP treatment, caspase-3 activity in the NPCs increased. However, exposing TBHP-induced NPCs to the EPSC-derived CM reduced oxidative stress, caspase-3 activity, cell apoptosis, fi brotic response, and cytokine production. Additionally, the EPSC-derived CM contained a higher concentration of Areg compared to that in the NPCs. Furthermore, Areg decreased oxidative stress, cell apoptosis, fi brosis, and infl ammation via both PI3K/AKT and ERK1/2 signaling pathways. Conclusion ECSCs reduce NPC apoptosis, oxidative stress, production of infl ammatory factors, and fi brotic response via the release of Areg. Moreover, Areg can exert these protective eff ects on NPCs via PI3K/AKT and ERK1/2 signaling pathways.