2. Academic Validation
  3. Targeting ZDHHC12-mediated PARP1 palmitoylation potentiates PARP inhibitor cytotoxicity

Targeting ZDHHC12-mediated PARP1 palmitoylation potentiates PARP inhibitor cytotoxicity

  • Cell Rep. 2026 Feb 24;45(2):116910. doi: 10.1016/j.celrep.2025.116910.
Xining Zhang 1,  Ye Liu 2,  Xingming Liao 3,  Min Wang 1,  Jiao Liu 1,  Yuemei Wen 3,  Rongdiao Liu 4,  Xiaolin Sang 4,  Guohui Li 2,  Pixu Liu 5,  Huiying Chu 6,  Hailing Cheng 7
Affiliations

Affiliations

  • 1 Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China.
  • 2 Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, China.
  • 3 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China.
  • 4 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; NHC Key Laboratory of Clinical Nutrition and Intervention, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; NHC Key Laboratory of Clinical Nutrition and Intervention, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: [email protected].
  • 6 Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, China. Electronic address: [email protected].
  • 7 Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China. Electronic address: [email protected].
PMID: 41581148 DOI: 10.1016/j.celrep.2025.116910
Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) elicit cytotoxicity by trapping PARP1 at DNA lesions, but clinical resistance remains a major challenge. Here, we identify reversible S-palmitoylation as a negative regulator of PARP1 chromatin engagement. Mass spectrometry reveals PARP1 palmitoylation at conserved cysteines within its DNA-binding domains. DNA damage reduces PARP1 palmitoylation, enhancing DNA binding, whereas inhibition of depalmitoylases APT1/2 elevates palmitoylation and suppresses DNA binding. The palmitoyltransferase ZDHHC12 catalyzes PARP1 palmitoylation, and its inhibition, along with the blockade of palmitate synthesis or global palmitoylation, augments PARP1 trapping and sensitizes high-grade ovarian Cancer (HGSOC) cells to the PARPi Niraparib. Patient-derived PARP1 variants R138C and R591C display hyper-palmitoylation, impaired trapping, and PARPi resistance through an indirect mechanism independent of palmitoylation at the mutation sites. ZDHHC12 knockdown restores PARP1 trapping and resensitizes resistant cells and xenografts to Niraparib. These findings establish ZDHHC12-mediated PARP1 palmitoylation as a targetable vulnerability to overcome PARPi resistance.

Keywords

CP: cancer; CP: molecular biology; DNA damage; Niraparib; PARP inhibitor; PARP1 palmitoylation; PARP1 trapping; ZDHHC12; ovarian cancer.

Figures
Products