PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2

Cells that detach from the extracellular matrix (ECM) undergo various forms of cell death, including ferroptosis. Previous studies have demonstrated that prostate cancer (PCa) cells undergo ferroptosis following ECM detachment, and resistance to ferroptosis may facilitate tumor metastasis. Pyruvate dehydrogenase E1 alpha 1 (PDHA1) has been identified as a key regulator in the progression of several malignancies; however, its role in ferroptosis and prostate cancer metastasis remains unclear. In this study, anoikis resistance (AnoR) prostate cancer cells exhibited a substantial increase in PDHA1 expression, which enhanced their survival and metastatic potential by increasing resistance to ferroptosis. Mechanistically, nuclear PDHA1 in AnoR cells facilitated histone H3 lysine 9 acetylation (H3K9Ac) that significantly accumulated at the promoter region of peroxisome proliferator-activated receptor alpha (PPARA), thereby upregulating its expression. PPARA, in turn, activated the transcription of apoptosis-inducing factor mitochondria-associated 2 (AIFM2), whose upregulation inhibited ferroptosis in AnoR prostate cancer cells. This study demonstrates that PDHA1 expression is found to be elevated in primary tumors from patients with metastatic prostate cancer. Additionally, the aberrant overexpression of PDHA1 in AnoR prostate cancer cells upregulates PPARA and AIFM2 expression through nuclear translocation, collectively suppressing ferroptosis and promoting metastasis. These findings reveal a novel role for PDHA1 in mediating ferroptosis resistance during ECM detachment and provide a potential therapeutic target for prostate cancer treatment.