{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:23:14Z","timestamp":1786116194964,"version":"build-2736575974"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Castration-resistant prostate cancer (CRPC) remains the lethal endpoint of prostate cancer progression, driven by the persistence and adaptive reprogramming of androgen receptor (AR) signaling under therapeutic pressure. Although AR\u2013ferroptosis crosstalk has been increasingly recognized, current models are largely descriptive and fail to explain why ferroptosis escape becomes a stable feature of resistant disease. Here, we propose that in CRPC, AR signaling functions not merely as a molecular regulator, but as the dominant state organizer of ferroptosis resistance, whereas ferroptosis influences AR primarily through a special feedback modulation rather than as an initiating driver of resistance evolution. We further suggest that this state can be understood through the concept of a ferroptosis threshold, which is shaped by AR across four interconnected axes: anti-ferroptotic defense, membrane lipid substrate ecology, edox buffering and iron toxicity boundary. Within this framework, mitochondria emerge not as passive effectors, but as central integrative hubs that couple metabolic rewiring, iron handling, reactive oxygen species control, and organelle communication to consolidate ferroptosis resistance. Building on this view, we propose a temporal model of AR-driven ferroptosis escape in CRPC, spanning an early vulnerability window after AR pathway inhibition, a phase of adaptive anti-ferroptotic reconstruction, and the eventual establishment of a resistant steady state. This model provides a theoretical basis for stage-specific therapeutic intervention. It supports both \u201cearly interception\u201d during the vulnerability window and \u201clate-state destabilization\u201d after resistant homeostasis has been established. In addition, it provides a rationale for biomarker-guided dynamic monitoring and temporally informed combination therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fonc.2026.1884640","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T07:59:36Z","timestamp":1786003176000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Androgen receptor signaling organizes ferroptosis escape in castration-resistant prostate cancer: a threshold-based model for therapeutic timing"],"prefix":"10.3389","volume":"16","author":[{"given":"Canlin","family":"Wang","sequence":"first","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinting","family":"Lv","sequence":"additional","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical 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