3-Hydroxy-β-ionone Suppresses Breast Cancer Progression by Inducing Apoptosis and Blocking EMT Through the TGF-β/Smad Signaling Pathway

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options and a poor prognosis. Epithelial-to-mesenchymal transition (EMT) plays a critical role in promoting TNBC metastasis. The natural bioactive substance 3-hydroxy-β-ionone (3-HBI), which has been studied in other cancer types, has not yet been examined in TNBC. This study investigates its potential mechanisms in TNBC cells through a combination of computational and experimental approaches, focusing on apoptosis induction and EMT inhibition. Molecular docking and molecular dynamics simulations demonstrated strong and stable binding of 3-HBI to key apoptosis-related proteins (Bcl-2, Bax, caspase-3) and EMT regulators (Smad2, Smad3). In vitro, 3-HBI significantly reduced cell viability in MDA-MB-231, T47D, and MCF7 cells, with IC<inf>50</inf> values of 388.40, 185.50, and 113.40 µg/mL, respectively. Moreover, 3-HBI suppressed clonogenic potential, induced apoptosis, and inhibited both migration and invasion. Molecular analysis showed increased expression of Bax, caspase-3, and E-cadherin, and reduced levels of Bcl-2, Smad2, Smad3, and N-cadherin. These findings provide the first mechanistic evidence that 3-HBI exerts anti-TNBC effects by promoting apoptosis and suppressing EMT, highlighting its potential as a promising therapeutic candidate for TNBC treatment.