Abstract Prostate cancer is the second most common malignancy among men, with androgen deprivation therapy (ADT) serving as the standard treatment due to the hormone sensitivity of prostate tumors. However, therapeutic resistance frequently develops, leading to castration-resistant prostate cancer (CRPC), an aggressive and lethal disease. A recently defined subtype, stem cell-like CRPC (CRPC-SCL), accounts for approximately 25% of CRPC cases and demonstrates poor responsiveness to ADT. CRPC-SCL is characterized by the expression of CD44, a glycoprotein that promotes hyaluronic acid binding and uptake. Single-cell RNA sequencing (scRNA-seq) analysis of CRPC patient samples revealed that CD44hi cells are predominantly enriched within a specific cluster and exhibit distinct stem cell-like characteristics. Functionally, in a CRPC-SCL patient-derived xenograft (PDX) model, the CD44hi subpopulation demonstrated enhanced tumorigenic and proliferative capacities, indicating that these cells represent a more aggressive and malignant fraction within the CRPC-SCL tumor. Mechanistically, iron metabolism emerged as a critical regulator of CD44hi cell function. These cells maintain elevated intracellular iron levels, which can translocate into the nucleus to activate the H3K9me2 demethylase KDM3A. Activation of KDM3A sustains CD44 expression and reinforces stem cell-like properties through modulation of H3K9me2 histone modification. Exploiting this metabolic vulnerability, inhibition of the iron-regulatory factor NRF2 was found to decrease ferritin expression and increase intracellular free iron. The resultant iron overload selectively induces ferroptosis in CD44hi cells. Collectively, these findings reveal that targeting iron metabolism to trigger ferroptotic cell death represents a promising therapeutic strategy for the treatment of CRPC-SCL. Citation Format: Wanli Cheng, Andrea Brunello, Panagiotis Chouvardas, Sofia Karkampouna, Marianna Kruithof-de. Julio. Iron Metabolism as a Therapeutic Vulnerability in Stem Cell-Like Castration-Resistant Prostate Cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B011.
Cheng et al. (Tue,) studied this question.