Abstract Prostate cancer (PCa) remains a global health challenge, with oxidative stress playing a critical role in its progression. High Mobility Group A2 (HMGA2), a chromatin architectural protein, has been implicated in increasing oxidative stress and sensitivity to ferroptosis inducers, though its mechanisms remain unclear. This study explored the role of HMGA2 in regulating GPX4, a key antioxidant enzyme, and its impact on oxidative stress and ferroptosis sensitivity in PCa cells. Using UALCAN database analysis, western blot, and lipid peroxidation assays, we investigated HMGA2-GPX4 interactions in various PCa cell lines, including enzalutamide-resistant C4-2B MDVR cells. Our findings revealed that high HMGA2 and low GPX4 expression are linked to higher Gleason scores and lower survival rates in prostate adenocarcinoma patients. Conversely, low/moderate HMGA2 expression correlates with higher GPX4 levels and improved survival. While cell lines showed a moderate inverse correlation between HMGA2 and GPX4, PC3 and DU145 cells exhibited elevated lipid peroxides, consistent with high HMGA2 and low GPX4 expression. Overexpression experiments demonstrated that wild-type HMGA2 increases GPX4 expression, while truncated HMGA2 reduces GPX4 levels, leading to heightened lipid peroxidation and ferroptosis sensitivity. Interestingly, GPX4 regulation appears to involve post-translational mechanisms, as SLC7A11 mRNA levels increased in both cases. Enzalutamide-resistant C4-2B MDVR cells, with elevated HMGA2 and GPX4 levels, were more sensitive to the ferroptosis inducer RSL3, a sensitivity partially reversed by ferrostatin-1. HMGA2 knockdown further increased GPX4 in these cells but did not significantly alter their ferroptosis susceptibility. In summary, HMGA2 plays a complex role in GPX4 regulation, with truncated HMGA2 enhancing oxidative stress and ferroptosis sensitivity. These findings highlight the therapeutic potential of targeting ferroptosis in aggressive and treatment-resistant PCa. Citation Format: Precious Elechi. Dike, Valerie Odero-Marah, Bor-Jang Hwang, Mojisoluwa Awolowo, Bethtrice Elliott, Taaliah Campbell. HMGA2 as a ferroptosis regulator: Implications for targeted therapy in prostate cancer abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A033.
Dike et al. (Thu,) studied this question.