{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:26:13Z","timestamp":1792106773568,"version":"4.4.0"},"reference-count":67,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Young Investigator Research Grant from the KOREAN NEPHROLOGY RESEARCH FOUNDATION"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: \u201crobustness through redundancy\u201d in defense systems and the \u201cevolutionary arms race\u201d between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically \u201ccold\u201d prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions.<\/jats:p>","DOI":"10.3390\/antiox14121517","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T13:45:07Z","timestamp":1766065507000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploiting Oxidative Stress as Achilles\u2019 Heel: From Redox Homeostasis to Ferroptosis in Prostate Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8789-575X","authenticated-orcid":false,"given":"Sanghyeon","family":"Yu","sequence":"first","affiliation":[{"name":"Translational-Transdisciplinary Research Center, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul 05278, Republic of Korea"},{"name":"Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02453, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Baek","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taesoo","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1507-9829","authenticated-orcid":false,"given":"Man S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Translational-Transdisciplinary Research Center, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul 05278, Republic of Korea"},{"name":"Center for Space Biomedical Science, NEXUS Institute, Kyung Hee University, Yongin-si 17104, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","unstructured":"GBD 2023 Diseases and Injuries Collaborators (2025). 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