<i>HOXD-AS1</i> interacting with AMPK causes a disturbance in mTOR signaling, impairing ferroptosis in glioma

Ferroptosis, a recently discovered form of cell death, plays an important role in cancer progression. It has been reported that ferroptosis plays a complex regulatory role in the biological processes of glioma. In glioma, the long noncoding RNA, HOXD cluster antisense RNA 1 (<i>HOXD-AS1</i>), functions as an oncogene, contributing to glioma progression. However, its potential functions in ferroptosis are unclear. Herein, we aimed to clarify the biological function and detailed molecular mechanism of <i>HOXD-AS1</i> in regulating ferroptosis in glioma. Firstly, cell viability, reactive oxygen species (ROS), and malondialdehyde (MDA) content assays were detected. The mechanisms of <i>HOXD1-AS1</i>'s effect on ferroptosis were evaluated by detecting glutathione, Cys, and solute carrier family 7 member 11 (SLC7A11) levels. RNA immunoprecipitation and RNA pull-down techniques were employed to explore whether <i>HOXD-AS1</i> can directly bind AMP-activated protein kinase (AMPK). Our findings indicated that <i>HOXD-AS1</i> levels were augmented significantly in glioma tissue. <i>HOXD-AS1</i> knockdown induced MDA and ROS accumulation, subsequently resulting in ferroptosis. Further molecular analysis showed that the binding between <i>HOXD-AS1</i> and AMPK regulated the mechanistic target of rapamycin kinase pathway, inhibit the transport of Cys, and decrease the production of glutathione, eventually resulting in ferroptosis. Our study revealed that <i>HOXD-AS1</i> regulates cell ferroptosis, thus its downregulation might be an effective strategy to suppress glioma.