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While S\u2010palmitoylation of lipid peroxide\u2010scavenging proteins such as GPX4 and SLC7A11 has been shown to suppress ferroptosis, whether palmitoylation modulates the lipid peroxidation generation remains unclear. Here, we identified the palmitoyltransferase ZDHHC2 as a critical driver of enzalutamide resistance through destabilizing ACSL4. ZDHHC2 is transcriptionally upregulated by a FOXA1\/CXXC5\/TET2 complex and promotes S\u2010palmitoylation of the deubiquitinase USP19, which impairs its interaction with ACSL4. This disrupts USP19\u2010mediated ACSL4 stabilization, promoting its ubiquitin\u2013proteasome degradation and consequently suppressing lipid peroxidation and ferroptosis. We synthesized a small\u2010molecule ZDHHC2 inhibitor, TTZ1, which restores ACSL4 protein, reactivates ferroptosis, and reverses enzalutamide resistance in CRPC cell lines and patient\u2010derived xenograft models. This study uncovers a previously unrecognized mechanism by which palmitoylation regulates ferroptosis through modulating ACSL4 stability, and highlights the ZDHHC2\u2010USP19\u2010ACSL4 axis as a druggable target for overcoming resistance in advanced prostate cancer.<\/jats:p>","DOI":"10.1002\/advs.202514077","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T11:05:01Z","timestamp":1761217501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["ZDHHC2\u2010Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuai","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Urology The Second Xiangya Hospital Central South University  Changsha Hunan 410011 China"},{"name":"Key Laboratory of Diabetes Immunology 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