c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer

Abstract Prostate cancer is a highly heterogeneous malignancy, with distinct subtypes displaying unique molecular and metabolic profiles. This study identifies a compensatory shift in α-ketoglutarate (α-KG) metabolism in prostate cancer, where the tumor relies on IDH1 to incorporate citrate into the TCA cycle. IDH1 inhibition, leads to lower α-KG levels. Since α-KG is required for HIF-1α hydroxylation, IDH1 inhibition stabilizes HIF-1α, which subsequently upregulates c-Fos. C-Fos enhances GLUD1 transcription, promoting the conversion of glutamate to α-KG as a compensatory mechanism. Additionally, c-Fos upregulates downstream effectors, including FOXC1 and SOX2, driving neuroendocrine differentiation in prostate cancer. Targeting α-KG-metabolizing enzymes, such as IDH1 or GLUD1, presents promising therapeutic strategies for prostate cancer subtypes by inhibiting tumor proliferation and inducing oxidative stress, thus sensitizing tumors to ferroptosis. Overall, these findings uncover a metabolic adaptation in response to IDH1 inhibition and highlight the pivotal role of c-Fos in mediating this compensatory pathway, offering new insights into potential metabolic targets for prostate cancer treatment and ferroptosis-based therapies.