Molecular Insights into the Potential Anticancer Activity of Pyrone Derivatives.

Pyrone derivatives, characterized by a six-membered lactone, exhibit multifaceted anticancer activity by targeting PI3K/Akt/mTOR, MAPK/ERK, Wnt/β-catenin, and Hedgehog pathways. They suppress cancer proliferation of various cancer cells, while inducing apoptosis through mitochondrial dysfunction and caspase activation. These compounds arrest cell cycle, downregulate cancer stemness markers, and reverse multidrug resistance and enhance chemosensitivity. Preclinical studies highlight efficacy in xenograft models, particularly against KRAS-mutated and therapy-resistant cancers, with synergistic effects when combined with chemo-/radiotherapy. Pyrone derivatives also impair angiogenesis by suppressing VEGF signaling. However, poor solubility and bioavailability, coupled with off-target toxicity hinder clinical translation. Emerging strategies, such as nanoparticle delivery, structural modifications, and immunotherapy combinations, aim to address these limitations. Their ability to disrupt oncogenic signaling, overcome resistance, and target cancer stem cells underscores their therapeutic potential. Future research should focus on pharmacokinetic refinement, toxicity profiling, and clinical validation to advance their application in precision oncology.