Sesquiterpenoids target IFIT family proteins and LIMK1: potential implications for the tumor microenvironment and macrophage infiltration.

BACKGROUND: Sesquiterpenoids and their derivatives have exhibited promising inhibitory effects against various types of cancers. However, the precise molecular targets and their interplay with the tumor microenvironment (TME) remain elusive. METHODS: Transcriptomic data from GEO (kidney cancer, colon cancer, and acute myeloid leukemia) were analyzed to identify differentially expressed genes (DEGs) induced by sesquiterpenoids. Robust hub genes were identified using multiple algorithms (e.g., MCC) and validated using TCGA and GTEx datasets. The association between these hub genes and immune cell infiltration was evaluated via ssGSEA. RESULTS: The study identified the IFIT family, LIMK1, and HERC6 as key hub genes associated with sesquiterpenoid treatment. Single-cell RNA-seq analysis suggested these genes are predominantly enriched in mononuclear macrophages within the TME. Experimental validation confirmed that Sesquiterpenoids (Costunolide) inhibited the proliferation and migration of SW480 and A-498 cancer cells in a dose-dependent manner. Furthermore, Costunolide treatment upregulated IFN-γ and modulated LIMK1 expression and phosphorylation. CONCLUSION: This study highlights IFIT proteins and LIMK1 as potential targets of sesquiterpenoids. These findings provide insights into how sesquiterpenoids might influence cancer progression and correlate with macrophage infiltration, suggesting their potential as therapeutic agents. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15717-9.