ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Ferroptosis at the Metabolic-Immune Interface in Metastatic Castration-Resistant Prostate Cancer: Mechanistic Evidence, Translational Gaps, and Combination Strategies.Annals of surgical oncology · 2026Review
- Transcriptomic analysis of palmitoylation-related genes reveals a preferential association with BCAA catabolism in adipose tissue from pediatric obesity.Endocrine connections · 2026Article
- Deubiquitinating enzymes-mediated post-translational modifications of ferroptosis regulates cancer drug resistance.Discover oncology · 2026Review
- Dual regulation of metabolic reprogramming and protein competitive modifications: the core role and mechanism of MRPL36 in glioblastoma malignant progression.Journal of experimental & clinical cancer research : CR · 2026Article
- Protein modification systems as cancer biomarkers and therapeutic targets.Precision clinical medicine · 2026Review
- From lipid modification to cell death: the diverse roles of S-palmitoylation in cell fate decisions.Cell communication and signaling : CCS · 2026Review
- Targeting the FTO-ACSL4 Pathway: A Novel Mechanism for Sanguinarine Chloride-Induced Ferroptosis in Endometrial Cancer.Biomedicines · 2026Article
- ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Scoparone-Induced Phase Separation of ZDHHC12 Drives Ferroptosis via ATG12 S-palmitoylation and Ferritinophagy in Liver Fibrosis.Research (Washington, D.C.) · 2026Article
- S-palmitoylation of MTDH regulates ferroptosis resistance in breast cancer cell.Journal of lipid research · 2026Article
- The palmitoylation code in cell death signaling: from molecular mechanisms to therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
- Long Non-Coding RNA PVT1 Promotes Doxorubicin Resistance by Inhibiting Ferroptosis in Breast Cancer.Breast cancer (Dove Medical Press) · 2026Article
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Authors and funding
11 authors.
Funding
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 synthesized 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.
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