miR-130a-3p regulates the occurrence and progression of lung squamous cell carcinoma by activating ZDHHC5 and immune...

Prior investigations have indicated that the process of palmitoylation is crucial in the onset and progression of a variety of cancers. Nonetheless, its function in lung squamous cell carcinoma (LUSC) and the corresponding upstream and downstream regulatory networks remains inadequately explored. In this research, we aimed to elucidate the causal links and underlying mechanisms among microRNAs (miRNAs), palmitoylation-related genes, immune cell interactions, and LUSC using Mendelian randomization (MR) approaches. The study integrated 2-sample MR analysis, SMR analysis, differential gene expression examination, meta-analysis, single-cell investigation, and mediation assessment. Two-sample MR was employed to evaluate the causal impact of palmitoylation-associated genes on LUSC development, while SMR techniques and single-cell analyses were utilized to validate the association between gene expression patterns and LUSC. A notable positive association was observed between elevated expression levels of the ZDHHC5 gene and increased LUSC risk. Specifically, an increment of 1 standard deviation in ZDHHC5 expression corresponded to a 22.90% rise in LUSC risk. These findings were corroborated by differential gene expression analysis, meta-analysis, and validation at the single-cell level. Additional miRNA analysis revealed that miR-130a-3p indirectly influences LUSC development by modulating ZDHHC5 gene expression, with a mediation effect ratio of 95.67% (P = .038). Further mediation analysis explored the intermediary role of immune cells in the relationship between ZDHHC5 and LUSC, identifying CD28 on secreting regulatory T cells (Treg) with a mediation effect ratio of 16.59% (P = .033). The data indicate that miR-130a-3p exerts regulatory control over the ZDHHC5 gene, consequently modulating the function of CD28 on secreting Tregs, thereby promoting LUSC occurrence. These insights provide a novel theoretical foundation for the development of immunotherapeutic and targeted treatment strategies for LUSC.