化疗耐药仍然是限制骨肉瘤治疗的主要障碍，严重影响青少年骨肉瘤患者的预后。最近，据报道长非编码RNA（lncRNA）参与化疗耐药，而lncRNA导致骨肉瘤化疗耐药的机制仍不清楚。这里，LINC00520被鉴定为骨肉瘤中一种新型的顺铂耐药相关lncRNA，其高表达与骨肉瘤患者的不良预后相关。从功能上讲，LINC00520 可以在体外和体内增强骨肉瘤对顺铂的耐药性。从机制上讲，LINC00520与ENO1结合，通过阻断FBXW7介导的ENO1泛素化和蛋白酶体降解来上调ENO1蛋白表达，从而促进糖酵解并最终诱导骨肉瘤中的顺铂耐药。此外，METTL3 可以在骨肉瘤中以 m6A-YTHDF2 依赖性方式稳定和上调 LINC00520。这项研究提出了一种新的 lncRNA 驱动的骨肉瘤顺铂耐药机制，并提供了一种通过靶向 METTL3/LINC00520/ENO1/糖酵解轴来逆转骨肉瘤化疗耐药的有前景的治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Chemoresistance remains the main obstacle limiting the treatment of osteosarcoma, seriously affecting the prognosis of adolescent patients with osteosarcoma. Recently, long non-coding RNAs (lncRNAs) were reported to be involved in chemoresistance, while the mechanisms of lncRNAs underlying osteosarcoma resistance to chemotherapy remain elusive. Here, LINC00520 was identified as a novel cisplatin resistance-related lncRNA in osteosarcoma, and its high expression was associated with poor prognosis of osteosarcoma patients. Functionally, LINC00520 could potentiate osteosarcoma resistance to cisplatin in vitro and in vivo. Mechanistically, LINC00520 bound to ENO1 and upregulated ENO1 protein expression by blocking FBXW7-mediated ENO1 ubiquitination and proteasomal degradation, thereby promoting glycolysis and ultimately inducing cisplatin resistance in osteosarcoma. Furthermore, METTL3 could stabilize and upregulate LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma. This study proposes a novel lncRNA-driven mechanism for cisplatin resistance in osteosarcoma, and offers a promising therapeutic strategy for reversing chemoresistance in osteosarcoma by targeting the METTL3/LINC00520/ENO1/glycolysis axis.Copyright © 2024. Published by Elsevier B.V.