Parthenolide suppresses colorectal adenoma progression by restraining mast cell degranulation-associated epithelial remodeling

Background: Colorectal adenomas are major precursors of colorectal cancer, yet pharmacological strategies for intercepting adenoma progression remain limited. Increasing evidence suggests that immune–epithelial interactions contribute to early neoplastic remodeling; however, the role of mast cells in this process and their therapeutic relevance remain incompletely understood. Purpose: This study aimed to identify potential therapeutic compounds for colorectal adenoma and to investigate the cellular and molecular mechanisms underlying their effects. Methods: Single-cell transcriptomic analysis was integrated with A Single-cell Guided Pipeline to Aid Repurposing of Drugs (ASGARD) to identify candidate compounds for colorectal adenoma. The therapeutic efficacy of parthenolide (PTL) was evaluated in Apc^{Min/ +} mice by histopathological analyses. Single-cell RNA sequencing, epithelial subclustering, pseudotime analysis, pathway enrichment, and cell-cell communication analysis were subsequently performed to characterize PTL-associated remodeling of the adenoma microenvironment. Mast-cell activation and degranulation were further examined using cellular assays, and mast cell-epithelial interactions were investigated using conditioned medium and organoid models. Results: ASGARD analysis prioritized PTL as a candidate compound capable of reversing adenoma-associated transcriptional alterations. PTL treatment alleviated pathological abnormalities and aberrant epithelial proliferation in Apc^{Min/ +} mice. Single-cell analysis revealed remodeling of epithelial states during adenoma development, characterized by alterations in progenitor-like and Wnt-responsive epithelial populations, which were partially reversed following PTL treatment. Notably, adenoma progression was associated with a mast-cell transcriptional state enriched in granule-related programs. This mast-cell signature correlated with the abundance of Wnt-responsive epithelial cells, linking mast-cell activation to epithelial-state remodeling. PTL treatment attenuated these alterations. Conclusion: These findings identify PTL as a potential pharmacological intervention for colorectal adenoma and suggest that its therapeutic effects involve modulation of mast cell–epithelial interactions and aberrant epithelial remodeling. Together, these findings support PTL as a potential intervention for colorectal adenoma and suggest that restraining mast-cell degranulation may contribute to its protective effects.