Coumarins as modulators of autophagy and PI3K/mTOR signaling: implications for next-generation cancer therapies

BACKGROUND: Aberrant regulation of autophagy and persistent activation of the phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) signaling axis are recognized hallmarks of cancer progression, therapeutic resistance, and disease relapse. Coumarins, a chemically diverse class of natural and synthetic benzopyranone derivatives, have recently emerged as promising modulators of both autophagy and PI3K/mTOR signaling, positioning them as attractive candidates for next-generation anticancer strategies. AIM: This review critically examines current evidence on the ability of coumarin derivatives to regulate autophagy and PI3K/mTOR signaling in cancer, with emphasis on their mechanistic intersections, therapeutic implications, and translational potential. METHODS: A structured and integrative analysis of preclinical studies was conducted using major scientific databases, including PubMed, Scopus, and Web of Science. Relevant articles were identified using combinations of keywords such as "coumarins", "autophagy", "PI3K/mTOR", and "cancer". Only peer-reviewed studies written in English and reporting data from cellular or animal cancer models were included. Mechanistic evidence related to autophagy induction or inhibition, modulation of the PI3K/mTOR pathway, pharmacokinetic properties, safety considerations, and combination therapy strategies was systematically evaluated. RESULTS: Accumulating evidence demonstrates that coumarins can either induce or inhibit autophagic flux in a context-dependent manner, often through direct or indirect modulation of PI3K/mTOR signaling. These dual actions influence cancer cell survival, apoptosis, senescence, and sensitivity to chemotherapy. Several coumarins exhibit multitarget activity, addressing therapy resistance while maintaining favorable safety profiles. Emerging data further support their use in rational combination strategies and patient-stratified therapeutic approaches. CONCLUSION: Coumarins represent versatile molecular scaffolds capable of fine-tuning autophagy and PI3K/mTOR signaling in cancer. A deeper mechanistic understanding, alongside optimization of pharmacokinetics and patient stratification, will be essential for translating coumarin-based modulators into clinically effective anticancer therapies.