Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(m⁶A)-methylated modification regulates autophagy in IVDD-NPCs. Mechanistically, lysine methyltransferase 2A (KMT2A) promoted the expression of methyltransferase-like 3 (METTL3) through H3K4me3 modification, whereas METTL3-mediated m⁶A modification reduced the expression of autophagy-associated 4a (ATG4a) by attenuating its RNA stability, leading to autophagy damage in NPCs. Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs. Therefore, targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.

椎间盘退化 （IVDD） 是一种与衰老相关的疾病，其特征是随着 IVDD 的进展，衰老的髓核细胞 （NPC） 显着增加。然而，调节 NPC 衰老的具体机制仍然未知。在这项研究中，我们观察到 IVDD-NPC 自噬受损，这有助于 NPCs 衰老和衰老相关分泌表型 （SASP） 的上调。失调的 SASP 破坏了 NPC 的活力并启动了细胞外基质降解。相反，自噬的恢复通过抑制 GATA 结合蛋白 4 （GATA4） 逆转衰老表型。此外，我们做出了新的观察，即组蛋白 H3 赖氨酸 4 三甲基化 （H3K4me3） 修饰和 N6-甲基腺苷 （m⁶A） 甲基化修饰之间的串扰调节 IVDD-NPC 的自噬。从机制上讲，赖氨酸甲基转移酶 2A （KMT2A） 通过 H3K4me3 修饰促进甲基转移酶样 3 （METTL3） 的表达，而 METTL3 介导的 m⁶A 修饰通过减弱其 RNA 稳定性来降低自噬相关 4a （ATG4a） 的表达，导致 NPC 的自噬损伤。沉默 KMT2A 和 METTL3 增强了 IVDD-NPC 中的自噬通量并抑制了 SASP 表达。因此，靶向 H3K4me3 调节的 METTL3/ATG4a/GATA4 轴可能代表一种很有前途的 IVDD 新治疗策略。