Weilin Zhang, Kuize Liu, Zhencong Li, Dao Feng, Boyuan Zhou, Wei Zhao, Shengbang Huang, Zhiwen Dai, Jinguo Liang, Siyuan Chen, Yen Wei, Jinsong Wei
BACKGROUND: Intervertebral disc degeneration (IVDD) serves as the fundamental pathological basis for low back pain. Microplastics influence the organisms through exosomes-mediated communication. Our study aimed to investigate the roles and underlying mechanisms of polyethylene microplastics (PE-MPs) in intervertebral disc degeneration. METHODS: We isolated exosomes(exo) from PE-MPs-treated macrophages (M0-MPs-exo), and investigated whether PE-MPs could be translocated to nucleus pulposus cells (NPCs) via M0-MPs-exo, triggering ferroptosis and cellular senescence cascades that ultimately exacerbate IVDD progression. Then, the roles and underlying mechanisms of NAT10/SLC7A11 in IVDD were further explored in vitro and in vivo. RESULTS: M0-MPs-exo were successfully isolated, and PE-MPs could be transported to NPCs through M0-MPs-exo. Compared with the control NPCs, PE-MPs significantly up-regulated MMP13, P53 and P21 while down-regulated COL2A1, NAT10, GPX4 and SLC7A11 (P < 0.05). Besides, the increased levels of ROS and ac4C modification were also observed in NPCs treated with PE-MPs. Further, our in vitro and in vivo experiments displayed that NAT10 overexpression combined with ferrostatin-1 could significantly improve the PE-MPs-induced degenerative phenotypes, and ameliorate ferroptosis-related proteins, oxidative stress-related proteins, extracellular matrix (ECM) metabolism, and ac4C modification. Meanwhile, the effects of NAT10 in NPCs could be reversed by SLC7A11. Additionally, NAT10 overexpression could increase SOD and GSH levels, and reduce the levels of MDA, lipid peroxidation and Fe²⁺ in the PE-MPs-treated NPCs, which could be reversed by SLC7A11 knockdown. CONCLUSION: PE-MPs could be transported to NPCs via M0-MPs-exo, and trigger lipid peroxidation and ferroptosis through regulating NAT10/SLC7A11 and ac4C modification, thereby promoting IVDD.