β-Ionone for Cancer Therapy: Molecular Mechanisms, Apoptotic Signaling, Preclinical Evidence, and Translational Perspectives

β-Ionone is a naturally occurring C13-norisoprenoid apocarotenoid which is mainly derived from carotenoid cleavage and has gained significant attention due to its potential anticancer activity. Experimental investigations have shown that β-ionone has the ability to arrest the proliferation of cancer cells and to induce programmed cell death by several mechanisms depending on the type of tumors and experimental conditions. Mitochondrial apoptosis, such as Bax/Bcl-2 balance, cytochrome c release, activation of caspases, and p53-associated signaling, is the most consistently supported evidence for β-Ionone. Other mechanisms include modulation of the PI3K/Akt and MAPK/ERK signaling pathways, regulation of cell-cycle progression, generation of oxidative stress, and increased sensitivity to death-receptor-mediated apoptosis. Moreover, recent experimental studies have provided further support for the role of β-ionone in ferroptosis, as it was found to modulate the ferroptosis-associated proteins and Wnt/β-catenin signaling in gastric cancer models. By contrast, other mechanisms such as autophagy and the JAK/STAT3 signaling pathway are proposed mechanisms that need to be directly tested. Most importantly, evidence collected using β-ionone derivatives (such as esters and endoperoxides) differs from that collected from the parent. While promising preclinical results have been observed, translation is hampered by the lack of human pharmacokinetic data, uncertainties in bioavailability, and a lack of toxicity data and clinical trials. Target validation, characterization of the PHPD profile, safety assessment, formulation optimization, and clinically relevant in vivo validation should thus be given special attention in future studies.