Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed light on an unrecognized regulatory function of IGF2BP3 in ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in ferroptosis.

新出现的证据强调了 m6A 修饰对神经胶质瘤的多方面贡献。IGF2BP3 是一种 m6A 修饰读取蛋白，在转录后基因调控中起着至关重要的作用。尽管几项研究已确定 IGF2BP3 是神经胶质瘤的不良预后标志物，但其潜在机制仍不清楚。在这项研究中，我们证明了 IGF2BP3 敲低对神经胶质瘤细胞的细胞生长和存活有害。值得注意的是，我们发现 IGF2BP3 通过直接结合 GPX4 mRNA 上的特定基序来调节 GPX4 的蛋白表达水平，从而调节铁死亡。引人注目的是，发现该基序的 m6A 修饰对 GPX4 mRNA 的稳定性和翻译至关重要。此外，IGF2BP3敲除的神经胶质瘤细胞在小鼠异种移植模型中无法形成肿瘤，并且更容易受到小胶质细胞的吞噬作用。我们的研究结果揭示了 IGF2BP3 在铁死亡中未被认识的调节功能。在 GPX4 转录本中鉴定出关键的 m6A 位点阐明了转录后控制在铁死亡中的重要性。