Palmitoylation-mediated iron metabolism determines tumorigenesis in diffuse-type gastric cancer

Abstract Background Diffuse-type gastric cancer (DGC) is an aggressive subtype of gastric cancer with a poor prognosis and limited therapeutic options. Iron homeostasis is crucial for maintaining tumor cell survival and proliferation. S-palmitoylation, a prevalent post-translational lipid modification, has been implicated in tumor formation. However, whether S-palmitoylation affects iron metabolism and contributes to DGC pathogenesis remains largely unclear. Methods Bioinformatics analyses were performed to identify DGC-associated palmitoyltransferases. Transcriptome sequencing and functional experiments were used to evaluate the relationship between S-palmitoylation and iron metabolism. Mass spectrometry and methylated RNA immunoprecipitation sequencing were applied to explore the downstream regulatory mechanisms of S-palmitoylation. Results Multiple zinc finger DHHC-type palmitoyltransferases (ZDHHCs) were upregulated in DGC tissues, and pharmacological inhibition of S-palmitoylation suppressed DGC cell proliferation. Among the dysregulated ZDHHCs, ZDHHC9 exhibited the highest fold change. Elevated ZDHHC9 expression was connected to an unfavorable prognosis and could be useful for early diagnosis in DGC patients. Moreover, ZDHHC9-mediated S-palmitoylation promoted DGC growth in vitro and in vivo by increasing transferrin receptor 1 (TFRC) mRNA expression and enhancing cellular iron metabolism. Mechanistically, ZDHHC9 directly palmitoylated tRNA methyltransferase 61A (TRMT61A) at cysteine 204, thereby stabilizing the TRMT61A protein and facilitating its catalytic activity. This led to increased N 1 -methyladenosine (m 1 A) modification on TFRC mRNA and consequently enhanced TFRC mRNA stability. Conclusions This study identifies S-palmitoylation as a novel regulator of iron homeostasis and uncovers a previously unrecognized ZDHHC9–TRMT61A-TFRC axis in DGC. These findings provide mechanistic insights into DGC tumorigenesis and suggest potential therapeutic strategies for DGC.