Zdhhc14 promotes pyroptosis in the dorsal root ganglion of oxaliplatin‐induced peripheral neuropathy mice by enhancing GBP5 palmitoylation and suppressing its ubiquitination
- 1Department of Pharmacy Renmin Hospital of Wuhan University Wuhan Hubei China
- 2Department of Neurology, Suizhou Hospital Hubei University of Medicine Suizhou Hubei China
- 3Department of Neurology, The Sixth Hospital of Wuhan Affiliated Hospital of Jianghan University Wuhan Hubei China
Abstract
Background: Oxaliplatin‐related neuropathy (OIPN) remains a frequent chemotherapy‐induced complication, yet its underlying mechanisms remain incompletely understood. Emerging evidence implicates pyroptosis in OIPN pathogenesis, and palmitoylation has been recognised as a critical mechanism in neurological disorders.
Objective: This investigation set out to examine the part played by the palmitoyltransferase Zdhhc14 in pyroptosis in OIPN as well as to clarify the fundamental molecular processes.
Methods: A mouse model of OIPN was developed through intraperitoneal oxaliplatin administration, and primary neuronal cultures derived from dorsal root ganglia were exposed to oxaliplatin to simulate OIPN in vitro. Bioinformatics analysis was performed using the GSE255097 dataset. Gene and protein expression were examined by quantitative real‐time PCR, Western blot and immunofluorescence staining. Pyroptosis was assessed by lactate dehydrogenase release, flow cytometry and detection of pyroptosis‐related proteins. Co‐immunoprecipitation, immunoprecipitation and cycloheximide chase assay were applied to evaluate the mechanisms.
Results: Zdhhc14 was significantly up‐regulated in dorsal root ganglion (DRG) of OIPN mice in a time‐dependent manner. Zdhhc14 deficiency alleviated OIPN phenotypes, including mechanical hyperalgesia and cold allodynia, neuroinflammation and DRG pyroptosis. Mechanistically, Zdhhc14 binds to GBP5 and promotes its modification at Cys12, which is required for Zdhhc14‐mediated suppression of K48‐linked ubiquitination and subsequent proteasomal degradation, thereby stabilising GBP5. GBP5 knockdown phenocopied the protective effects of Zdhhc14 deficiency, whereas GBP5 overexpression reversed these effects. Importantly, mutation of the GBP5 palmitoylation site abolished the pro‐pyroptotic effects of Zdhhc14.
Conclusions: These findings indicate that the Zdhhc14/GBP5 palmitoylation axis critically regulates DRG pyroptosis and neuroinflammation in OIPN, identifying a novel mechanism and a potential mechanistic target warranting further translational evaluation for this debilitating condition.
Related
- PEGylated nicotinamide mononucleotide targeted ferroptosis in acute kidney injury by suppressing FAR1 palmitoylation in an ACAA1-dependent manner.
- Synergistic induction of pyroptosis-like cell death in colorectal cancer cells by norcantharidin and low-dose oxaliplatin promotes M1 macrophage polarization
- "It's Like a Marathon": A Qualitative Study of Symptom Burden and Adaptation Among Patients with Oxaliplatin-Induced Peripheral Neuropathy During Treatment.
- Emerging Therapeutic Targets in Oxaliplatin-Induced Acute Peripheral Neuropathy: Biochemical Protection by Organoselenium via Redox and Ionic Regulation.
- Baseline Peripheral Neuropathy Predicts Clinically Significant Neuropathy During Paclitaxel Treatment Following Oxaliplatin-based Chemotherapy.
BibTeX
@article{jiang2026zdhhc14,
title = {{Zdhhc14 promotes pyroptosis in the dorsal root ganglion of oxaliplatin‐induced peripheral neuropathy mice by enhancing GBP5 palmitoylation and suppressing its ubiquitination}},
author = {Xiao Jiang and Wanqiu Li and Yanzhuo Liu and Wei Song and Xuedan Zheng and Liu Tang},
journal = {Clinical and Translational Medicine},
year = {2026},
month = nov,
doi = {10.1002/ctm2.70874},
url = {https://doi.org/10.1002/ctm2.70874},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Zdhhc14 promotes pyroptosis in the dorsal root ganglion of oxaliplatin‐induced peripheral neuropathy mice by enhancing GBP5 palmitoylation and suppressing its ubiquitination
AU - Xiao Jiang
AU - Wanqiu Li
AU - Yanzhuo Liu
AU - Wei Song
AU - Xuedan Zheng
AU - Liu Tang
PY - 2026
DA - 2026/11/04
JO - Clinical and Translational Medicine
DO - 10.1002/ctm2.70874
UR - https://doi.org/10.1002/ctm2.70874
AB - Background: Oxaliplatin‐related neuropathy (OIPN) remains a frequent chemotherapy‐induced complication, yet its underlying mechanisms remain incompletely understood. Emerging evidence implicates pyroptosis in OIPN pathogenesis, and palmitoylation has been recognised as a critical mechanism in neurological disorders. Objective: This investigation set out to examine the part played by the palmitoyltransferase Zdhhc14 in pyroptosis in OIPN as well as to clarify the fundamental molecular processes. Methods: A mouse model of OIPN was developed through intraperitoneal oxaliplatin administration, and primary neuronal cultures derived from dorsal root ganglia were exposed to oxaliplatin to simulate OIPN in vitro. Bioinformatics analysis was performed using the GSE255097 dataset. Gene and protein expression were examined by quantitative real‐time PCR, Western blot and immunofluorescence staining. Pyroptosis was assessed by lactate dehydrogenase release, flow cytometry and detection of pyroptosis‐related proteins. Co‐immunoprecipitation, immunoprecipitation and cycloheximide chase assay were applied to evaluate the mechanisms. Results: Zdhhc14 was significantly up‐regulated in dorsal root ganglion (DRG) of OIPN mice in a time‐dependent manner. Zdhhc14 deficiency alleviated OIPN phenotypes, including mechanical hyperalgesia and cold allodynia, neuroinflammation and DRG pyroptosis. Mechanistically, Zdhhc14 binds to GBP5 and promotes its modification at Cys12, which is required for Zdhhc14‐mediated suppression of K48‐linked ubiquitination and subsequent proteasomal degradation, thereby stabilising GBP5. GBP5 knockdown phenocopied the protective effects of Zdhhc14 deficiency, whereas GBP5 overexpression reversed these effects. Importantly, mutation of the GBP5 palmitoylation site abolished the pro‐pyroptotic effects of Zdhhc14. Conclusions: These findings indicate that the Zdhhc14/GBP5 palmitoylation axis critically regulates DRG pyroptosis and neuroinflammation in OIPN, identifying a novel mechanism and a potential mechanistic target warranting further translational evaluation for this debilitating condition.
SN - 2001-1326
ER -