Integrated Proteomics and Single-Cell Transcriptomics Reveal the Molecular Mechanism by Which SERPINB6 Palmitoylation Drives Gastric Cancer Progression
YANG Jie1, BAI Junping2, GUO Fenghua3, AN Liwei2, ZHOU Zhaocai1*
Dysregulation of palmitoylation plays a pivotal role in tumorigenesis, progression, and therapeutic resistance, yet its aberrant regulatory network in gastric cancer remains elucidated. This study first identified significantly elevated activity of the ZDHHC enzyme family in gastric cancer tissues through analysis of the TCGA database, which correlated with poor patient prognosis and immunotherapy resistance. Subsequently, utilizing 4D label-free quantitative proteomics combined with metabolite-labeled click chemistry, palmitoylated proteins were screened in gastric cancer, identifying 495 palmitoylated proteins. Among these, SERPINB6 and PPA1 were markedly upregulated in tumors, while ALDH6A1 and GLUL were downregulated. Differential proteins were predominantly implicated in glycolytic reprogramming and redox homeostasis regulation. Single-cell transcriptomics analysis revealed that these proteins were enriched in tumor epithelial subpopulations. Key differential proteins, such as SERPINB6, driven by high expression, activated lipid metabolic pathways to promote fatty acid metabolism and remodeled intercellular communication networks: enhancing cell adhesion-related signaling to reinforce physical barriers, thereby fostering tumor cell drug resistance and immune evasion, while simultaneously suppressing T/NK cell function and promoting immune escape. These findings elucidate a dual mechanism by which palmitoylation protein SERPINB6 may drive gastric cancer progression through metabolic reprogramming and immune microenvironment crosstalk, providing novel directions for precision therapeutic strategies targeting this modification network.
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