New Insights into the Molecular Actions of Grosheimin, Costunolide, and α- and β-Cyclocostunolide on Primary Cilia Structure and Hedgehog Signaling

Sesquiterpene lactones (SLs) are plant-derived metabolites with recognized pharmacological properties. Dysfunction of the primary cilium (PC), a solitary sensory organelle essential for development, is associated with disorders such as ciliopathies and tumors. While previous studies have shown that certain SLs can alter PC structure in human retinal cells, their influence on ciliary signaling pathways remains unclear. In this study, we examined the effect of four SLs-grosheimin, costunolide, α-cyclocostunolide (α-C), and β-cyclocostunolide (β-C)-on ciliary function in human primary fibroblasts. Using immunofluorescence and qPCR to assess cilia structure and Hedgehog (Hh) pathway activation, we found that grosheimin enhanced ciliogenesis without affecting Hh signaling. In contrast, costunolide, α-C, and β-C disrupted ciliary structure and suppressed the Hh pathway transcripts <i>Gli1</i> and <i>Ptch1.</i> RNA sequencing revealed that grosheimin upregulated genes related to microtubule binding and ciliogenesis, whereas α-C downregulated tubulin subunit transcripts. These findings suggest distinct molecular mechanisms through which SLs affect ciliary structure and function. Collectively, this study highlights the potential of specific SLs as modulators of ciliary signaling, offering promising leads for therapeutic strategies targeting ciliopathies and tumors.