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. 2025 Oct 23:e14077.
doi: 10.1002/advs.202514077. Online ahead of print.

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

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 Zhu  1 , Lu Yi  1 , Yuan Li  1 , Yinhuai Wang  1 , Haojie Huang  5 , Xuewen Jiang  6   7   8 , Xin Jin  1   2   3   4
Affiliations

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

Shuai Shao et al. Adv Sci (Weinh). .

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.

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