Dysregulated growth factor receptor pathways, RNA modifications, and metabolism each promote tumor heterogeneity. Here, we demonstrate that platelet-derived growth factor (PDGF) signaling induces N⁶-methyladenosine (m⁶A) accumulation in glioblastoma (GBM) stem cells (GSCs) to regulate mitophagy. PDGF ligands stimulate early growth response 1 (EGR1) transcription to induce methyltransferase-like 3 (METTL3) to promote GSC proliferation and self-renewal. Targeting the PDGF-METTL3 axis inhibits mitophagy by regulating m⁶A modification of optineurin (OPTN). Forced OPTN expression phenocopies PDGF inhibition, and OPTN levels portend longer survival of GBM patients; these results suggest a tumor-suppressive role for OPTN. Pharmacologic targeting of METTL3 augments anti-tumor efficacy of PDGF receptor (PDGFR) and mitophagy inhibitors in vitro and in vivo. Collectively, we define PDGF signaling as an upstream regulator of oncogenic m⁶A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.

生长因子受体途径失调、RNA 修饰和代谢都会促进肿瘤异质性。在这里，我们证明血小板源性生长因子（PDGF）信号传导诱导胶质母细胞瘤（GBM）干细胞（GSC）中N ⁶ -甲基腺苷（m ⁶ A）的积累来调节线粒体自噬。PDGF 配体刺激早期生长反应 1 (EGR1) 转录，诱导甲基转移酶样 3 (METTL3)，从而促进 GSC 增殖和自我更新。靶向 PDGF-METTL3 轴通过调节 m ^{6抑制线粒体自噬}optineurin (OPTN) 的修饰。强制 OPTN 表达表现出 PDGF 抑制的表型，并且 OPTN 水平预示着 GBM 患者的生存期更长；这些结果表明 OPTN 具有肿瘤抑制作用。METTL3 的药理学靶向增强了 PDGF 受体 (PDGFR) 和线粒体自噬抑制剂的体外和体内抗肿瘤功效。总的来说，我们将 PDGF 信号传导定义为致癌 m ⁶ A 调节的上游调节因子，驱动肿瘤代谢以促进癌症干细胞维持，强调 PDGF-METTL3-OPTN 信号传导作为 GBM 治疗靶点。