Zdhhc14 promotes pyroptosis in the dorsal root ganglion of oxaliplatin‐induced peripheral neuropathy mice by enhancing GBP5 palmitoylation and suppressing its ubiquitination
Xiao Jiang, Wanqiu Li, Yanzhuo Liu, Wei Song, Xuedan Zheng, Liu TangAbstract
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.