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Although CRPC cells exhibit sensitivity to ferroptosis inducers, the mechanisms regulating ferroptosis remain unclear. Here, we identify nuclear factor I\/B (NFIB) as a critical suppressor of ferroptosis in CRPC. NFIB is upregulated in CRPC tissues and cell lines, positively correlating with SLC3A2, a critical subunit of System Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    . NFIB knockout enhances erastin\u2010induced ferroptosis, marked by elevated Fe\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    , MDA, and ROS levels. Mechanistically, NFIB directly activates SLC3A2 transcription and forms nuclear condensates through intrinsically disordered regions at both the N\u2010terminus (1\u201369) and C\u2010terminus (173\u2013495), with the C\u2010terminal IDR additionally supporting nuclear localization. Moreover, SIRT7\u2010dependent deacetylation of NFIB regulates acetylation at K65 within the N\u2010terminal IDR, thereby tuning condensate dynamics. K65 mutation reduces condensate liquidity and weakens NFIB\u2010driven SLC3A2 transcriptional activation, resulting in enhanced ferroptosis. In vivo, combined NFIB suppression and ferroptosis induction significantly inhibit tumor growth and increase lipid peroxidation in CRPC xenografts. These findings uncover a critical role of NFIB phase separation and acetylation in ferroptosis regulation and suggest NFIB as a promising therapeutic target in CRPC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202515340","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:02:10Z","timestamp":1773068530000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phase Separation of NFIB Suppresses SLC3A2\u2010Mediated Ferroptosis in Castration\u2010Resistant Prostate Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Qiunuo","family":"Li","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Cancer Hospital &amp; 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