Ferroptosis is a recently described mode of cell death caused by the accumulation of intracellular
iron and
lipid reactive oxygen species (ROS), which play critical roles in
tumorigenesis and
cancer progression. However, the underlying molecular mechanisms and promising
biomarkers of ferroptosis among
cancers remain to be elucidated. In this study, 30 ferroptosis regulators in ferroptosis-related signaling pathways were identified and analyzed in 33
cancer types. We found transcriptomic aberrations and evaluated the prognostic value of ferroptosis regulators across 33
cancer types. Then, we predicted and validated potential
transcription factors (including E2F7, KLF5 and FOXM1) and therapeutic drugs (such as
cyclophosphamide,
vinblastine, and
gefitinib) that target ferroptosis regulators in
cancer. Moreover, we explored the molecular mechanisms of ferroptosis and found that signaling pathways such as the
IL-1 and
IL-2 pathways are closely associated with ferroptosis. Additionally, we found that ferroptosis regulators have a close relationship with immunity-related parameters, including the immune score, immune cell infiltration level, and
immune checkpoint protein level. Finally, we determined a ferroptosis score using GSVA method. We found that the ferroptosis score effectively predicted ferroptotic cell death in
tumor samples. And ferroptosis score is served as an independent prognostic
indicator for the incidence and recurrence of
cancers. More importantly, patients with high ferroptosis scores received greater benefit from
immunotherapy. We aslo created an online webserver based on the nomogram prognostic model to predict the survival in
immunotherapy cohort. The reason for this outcome is partially the result of patients with a high ferroptosis rate also having high immune scores, HLA-related gene expression and
immune checkpoint protein expression, such as PDL2 and TIM3. Moreover, patients with high ferroptosis scores exhibited CD8 T cell and TIL infiltration and immune-related signaling pathway enrichment. In summary, we systematically summarize the molecular characteristics, clinical relevance and immune features of ferroptosis across
cancers and show that the ferroptosis score can be used as a prognostic factor and for the evaluation of
immunotherapy effects.