Lupane triterpenes isolated from Vasconcellea chilensis (wild papaya) inhibit colorectal cancer cell growth by targeting the Wnt/β-catenin signaling pathway.

Vasconcellea chilensis Planch. ex A. DC., an endemic Chilean wild relative of mountain papaya (V. pubescens) adapted to extreme coastal environments, is largely unexplored for fruit phytochemistry. The ethanol extract yielded six 27-O-caffeoyl lupane triterpenoids (1-6), including two novel C-28 methyl esters, vasconcellates A and B (5, 6), and one known lignan (7). This is the first report of caffeoyl lupanes in the Caricaceae family. Compounds 1-7 were evaluated for inhibition of the Wingless/Integrated (Wnt)/β-catenin signaling pathway in a colorectal cancer model. Compound 4 (27-O-E-caffeoylbetulinic acid) showed marked activity by disrupting Frizzled 4 (FZD4) and Dishevelled 1 (DVL1) interaction (EC₅₀ = 16.2 ± 1.1 μM), suppressing Wnt target gene transcription (IC₅₀ = 12.1 ± 0.7 μM), and reducing CaCo-2 cell proliferation by 40% at 30 μM after 48 h. Docking indicated binding to the FZD4 cholesterol pocket, suggesting allosteric modulation. These results identify V. chilensis fruit as a novel source of bioactive triterpenoids with potential for colorectal cancer prevention.