Abnormally Expressed Ferroptosis-Associated FANCD2 in Mediating the Temozolomide Resistance and Immune Response in Glioblastoma

Ferroptosis-related genes (FRGs) have been identified as potential targets involved in oncogenesis and cancer therapeutic response. Nevertheless, the specific roles and underlying mechanisms of FRGs in GBM and temozolomide (TMZ) resistance remain unclear. Through comprehensive bioinformatics, we found that ferroptosis-related Fanconi anemia complementation group D2 (FANCD2) was significantly up-regulated in GBM tissues, and the high expression level of FANCD2 was related to the poor prognosis in primary and recurrent GBM patients. Furthermore, FANCD2 could promote TMZ resistance by attenuating ferroptosis in GBM cells. Knockdown of FANCD2 could increase reactive oxygen species (ROS) levels and inhibit cell survival. The two characteristics were associated with ferroptosis in TMZ-resistant GBM cells T98G-R and U118-R. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed FANCD2 was potentially linked with several cancer-associated signaling pathways, including chromosome segregation, DNA replication, and cell cycle transition. In addition, we demonstrated that FANCD2 expression was positively correlated with several tumor-infiltrating lymphocytes (TILs) and multiple immune-associated signatures in GBM. Therefore, up-regulated FANCD2 could protect GBM cells from ferroptosis and promote TMZ resistance. FANCD2 may be a novel therapeutic target in GBM.