ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation

Shuai Shao; Wei Li; Yulong Hong; Ruijiang Zeng; Liang Zhu; Lu Yi; Yuan Li; Yinhuai Wang; Haojie Huang; Xuewen Jiang; Xin Jin

doi:10.1002/advs.202514077

ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation

Adv Sci (Weinh). 2025 Oct 23:e14077. doi: 10.1002/advs.202514077. Online ahead of print.

Authors

Shuai Shao^{1

2

3

4}, Wei Li^{1

2

3

4}, Yulong Hong^{1

2

3

4}, Ruijiang Zeng^{1

2

3

4}, Liang Zhu¹, Lu Yi¹, Yuan Li¹, Yinhuai Wang¹, Haojie Huang⁵, Xuewen Jiang^{6

7

8}, Xin Jin^{1

2

3

4}

Affiliations

¹ Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
² Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Disease, Changsha, 410011, China.
³ Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China.
⁴ Furong Laboratory, Changsha, Hunan, 410000, China.
⁵ Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
⁶ Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Jinan, 250200, China.
⁷ Key Laboratory of Urinary Precision Diagnosis and Treatment, Universities of Shandong, Jinan, 250200, China.
⁸ Shandong Provincial Engineering Research Center for Precision Diagnosis and Treatment of Urological and Male Reproductive Diseases, Jinan, 250200, China.

PMID: 41126755
DOI: 10.1002/advs.202514077

Abstract

Ferroptosis represents a promising vulnerability to overcome therapeutic resistance in castration-resistant prostate cancer (CRPC). While S-palmitoylation of lipid peroxide-scavenging 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-palmitoylation of the deubiquitinase USP19, which impairs its interaction with ACSL4. This disrupts USP19-mediated ACSL4 stabilization, promoting its ubiquitin-proteasome degradation and consequently suppressing lipid peroxidation and ferroptosis. We developed a small-molecule ZDHHC2 inhibitor, TTZ1, which restores ACSL4 protein, reactivates ferroptosis, and reverses enzalutamide resistance in CRPC cell lines and patient-derived xenograft models. This study uncovers a previously unrecognized mechanism by which palmitoylation regulates ferroptosis through modulating ACSL4 stability, and highlights the ZDHHC2-USP19-ACSL4 axis as a druggable target for overcoming resistance in advanced prostate cancer.

Keywords: ACSL4; CRPC; ZDHHC2; ferroptosis; lipid peroxide production.

Abstract

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