Lu Qian-Wei, Liao Yang
Department of Oncology and Hematology, The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth's People's Hospital of Chongqing, Chongqing, 400700, People's Republic of China.
Department of Oncology and Hematology, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, China.
Eur J Med Res. 2025 Jun 21;30(1):504. doi: 10.1186/s40001-025-02787-x.
Chemotherapy resistance poses a significant challenge in the initial treatment of acute myeloid leukemia (AML). Growth differentiation factor 15 (GDF-15) has been shown to play a critical role in cancer progression; however, the potential mechanisms by which GDF-15 contributes to AML progression and chemotherapy resistance remain unclear. We found that M2 macrophages secrete high levels of GDF-15, promoting resistance of AML cells to mitoxantrone (MTX). Furthermore, we demonstrated that MTX induces downregulation of the SLC7A11/GPX4 signaling axis in AML cells, mediating ferroptosis. GDF-15 enhances the expression of the SLC7A11/GPX4 axis, thereby inhibiting ferroptosis in AML cells and contributing to drug resistance. In addition, GDF-15 mitigates the decline in mitochondrial membrane potential and mitochondrial quality induced by MTX. In vivo experiments indicate that blocking GDF-15 effectively enhances the sensitivity of AML cells to mitoxantrone by reducing the expression of the SLC7A11/GPX4 axis.
化疗耐药性在急性髓系白血病（AML）的初始治疗中构成了重大挑战。生长分化因子15（GDF - 15）已被证明在癌症进展中起关键作用；然而，GDF - 15促进AML进展和化疗耐药性的潜在机制仍不清楚。我们发现M2巨噬细胞分泌高水平的GDF - 15，促进AML细胞对米托蒽醌（MTX）的耐药性。此外，我们证明MTX诱导AML细胞中SLC7A11/GPX4信号轴的下调，介导铁死亡。GDF - 15增强SLC7A11/GPX4轴的表达，从而抑制AML细胞中的铁死亡并导致耐药性。此外，GDF - 15减轻了MTX诱导的线粒体膜电位和线粒体质量的下降。体内实验表明，阻断GDF - 15可通过降低SLC7A11/GPX4轴的表达有效增强AML细胞对米托蒽醌的敏感性。
