BackgroundAs a new type of regulatory cell death, ferroptosis has been proven to be involved in cancer pathogenesis and therapeutic response. However, the detailed roles of ferroptosis or ferroptosis‐associated genes in glioma remain to be clarified.MethodsHere, we performed the TMT/iTRAQ‐Based Quantitative Proteomic Approach to identify the differentially expressed proteins between glioma specimens and adjacent tissues. Kaplan–Meier survival was used to estimate the survival values. We also explored the regulatory roles of abnormally expressed formin homology 2 domain‐containing protein 1 (FHOD1) in glioma ferroptosis sensitivity.ResultsIn our study, FHOD1 was identified to be the most significantly upregulated protein in glioma tissues. Multiple glioma datasets revealed that the glioma patients with low FHOD1 expression displayed favorable survival time. Functional analysis proved that the knockdown of FHOD1 inhibited cell growth and improved the cellular sensitivity to ferroptosis in glioma cells T98G and U251. Mechanically, we found the up‐regulation and hypomethylation of HSPB1, a negative regulator of ferroptosis, in glioma tissues. FHOD1 knockdown could enhance the ferroptosis sensitivity of glioma cells via up‐regulating the methylated heat‐shock protein B (HSPB1). Overexpression of HSPB1 significantly reversed FHOD1 knockdown‐mediated ferroptosis.ConclusionsIn summary, this study demonstrated that the FHOD1‐HSPB1 axis exerts marked regulatory effects on ferroptosis, and might affect the prognosis and therapeutic response in glioma.

Metal regulatory transcription factor 1 (MTF1) has been reported to be correlated with several human diseases, especially like cancers. Exploring the underlying mechanisms and biological functions of MTF1 could provide novel strategies for clinical diagnosis and therapy of cancers. In this study, we conducted the comprehensive analysis to evaluate the profiles of MTF1 in pan-cancer. For example, TIMER2.0, TNMplot and GEPIA2.0 were employed to analyze the expression values of MTF1 in pan-cancer. The methylation levels of MTF1 were evaluated via UALCAN and DiseaseMeth version 2.0 databases. The mutation profiles of MTF1 in pan-cancers were analyzed using cBioPortal. GEPIA2.0, Kaplan–Meier plotter and cBioPortal were also used to explore the roles of MTF1 in cancer prognosis. We found that high MTF1 expression was related to poor prognosis of liver hepatocellular carcinoma (LIHC) and brain lower grade glioma (LGG). Also, high expression level of MTF1 was associated with good prognosis of kidney renal clear cell carcinoma (KIRC), lung cancer, ovarian cancer and breast cancer. We investigated the genetic alteration and methylation levels of MTF1 between the primary tumor and normal tissues. The relationship between MTF1 expression and several immune cells was analyzed, including T cell CD8 + and dendritic cells (DC). Mechanically, MTF1-interacted molecules might participate in the regulation of metabolism-related pathways, such as peptidyl-serine phosphorylation, negative regulation of cellular amide metabolic process and peptidyl-threonine phosphorylation. Single cell sequencing indicated that MTF1 was associated with angiogenesis, DNA repair and cell invasion. In addition, in vitro experiment indicated knockdown of MTF1 resulted in the suppressed cell proliferation, increased reactive oxygen species (ROS) and promoted cell death in LIHC cells HepG2 and Huh7. Taken together, this pan-cancer analysis of MTF1 has implicated that MTF1 could play an essential role in the progression of various human cancers.

Ferroptosis is a cell death form that has been reported to be involved in the progression of gastric cancer (GC). However, the underlying mechanism of ferroptosis in GC still needs to be further explored. This study conducted a survey regarding the biological functions of ferroptosis-related gene AKR1C2 in GC. Multiple bioinformatic platforms were applied to indicate that the expression level of AKR1C2 was downregulated in GC tissues, which displayed good prognostic value. Clinical statistics proved that AKR1C2 expression was correlated with several tumor characteristics of GC patients, such as characteristics of N-stage tumor or residual tumor. Additionally, LinkedOmics was employed to explore the co-expression network and molecular pathways of AKR1C2 in GC. Eventually, AKR1C2 was found to be involved in several immune-related signatures, such as immunostimulators, immunoinhibitors, chemokines and chemokine receptors. To sum up, these results may provide a novel insight into the significance and biological functions of ferroptosis-related gene AKR1C2 in GC tumorigenesis.