ZDHHC13 prevents cuproptosis and enhances radioresistance in nasopharyngeal carcinoma cells by modulating FDX1 protein palmitoylation

Radioresistance is a major obstacle in antitumor therapies. This study explores the effects and functional mechanisms of zDHHC palmitoyltransferase 13 (ZDHHC13) on radioresistance in nasopharyngeal carcinoma (NPC). Bioinformatic and tumor tissue microarray analyses were performed to identify the expression pattern of ZDHHC13 in NPC. The parental C666-1 and HNE1 NPC cell lines were exposed to radiation to generate resistant cell lines (C666-1R and HNE1R). ZDHHC13 was silenced in these cell lines, followed by cell survival, proliferation, and apoptosis assays. The levels of copper ion metabolism-related factors, Cu+, and oxidative stress in the cells were determined to analyze cuproptosis activity. The interaction between ZDHHC13 and ferredoxin 1 (FDX1) was examined using immunoprecipitation and colocalization assays. Xenograft tumor models were established in mice for in vivo verification. ZDHHC13 was abundantly expressed in radioresistant NPC cells. ZDHHC13 knockdown enhanced the radiosensitivity of C666-1R and HNE1R cells, reduced cell proliferation, and promoted apoptosis under 5 Gy radiation exposure. Factors implicated in copper ion reduction, including FDX1, reduced in resistant cell lines. ZDHHC13 knockdown improved Cu+ levels and cuproptosis in cells. Treatment with tetrathiomolybdate, a copper chelator, blocked the oxidative stress and cuproptosis in C666-1R and HNE1R cells enhanced by ZDHHC13 silencing. Palmitoylation of FDX1 increased in radioresistant cells and decreased upon ZDHHC13 silencing. FDX1 silencing reduced cuproptosis and radiosensitivity in NPC cells. This study suggests that ZDHHC13 prevents cuproptosis and enhances radioresistance in NPC cells by modulating FDX1 palmitoylation.