Low back pain (LBP) is a common symptom of intervertebral disc degeneration (IDD). However, the pathogenesis of IDD is not well understood. Several studies have shown that patients with IDD experience aberrant changes in DNA methylation. 5-Azacytidine (5Aza) is a nucleoside-based DNA methyltransferase inhibitor that inhibits DNA methylation. Therefore, this study investigated whether 5Aza can improve the apoptosis of nucleus pulposus (NP) cells and ER stress (ERS) induced by il-1β by inhibiting PPARγ methylation and its potential pathogenesis. NP cell viability was detected using Cell Counting Kit-8 (CCK-8). Methylation-specific PCR (MSP) was used to evaluate the DNA methylation level. TUNEL was used to evaluate the apoptosis of NP cells. Western blot determined the expression levels of DNMT1, DNMT3a, PPARγ proteins, and ERS-related indexes (C/EBP homology protein (CHOP), GRP78, ATF-6) and apoptosis-related indexes (Bcl-2, Bax, Caspase-3) protein expression levels. 5Aza can inhibit the expression of DNMT1 and DNMT3a and promote PPARγ by modifying the methylation of PPARγ promoter. Western blot (Bcl-2, Bax, Caspase-3, CHOP, GRP78, ATF-6), TUNEL, and CHOP immunofluorescence results showed that 5Aza attenuated IL-1β-induced apoptosis and ERS of NP cells. When pretreated with PPARγ inhibitor (T0070907), the protective effect of 5Aza on IL-1β-induced apoptosis and ERS in NP cells is weakened, suggesting that 5Aza inhibits IL-1β-induced NP cell apoptosis and ERS by promoting the expression of PPARγ. 5Aza preserves PPARγ by inhibiting the expression of DNMT1/DNMT3a, which can significantly reduce IL-1β damage in NP cells. Our findings suggest that preserving PPARγ through DNA demethylation may be an attractive strategy for preventing or treating IDD.