Esculetin and its derivatives: recent advances in efficacy, mechanisms, and translational challenges

Esculetin (ESC, 6,7-dihydroxycoumarin), a naturally occurring polyphenolic coumarin found in numerous medicinal and dietary plants, has emerged as a multi-target bioactive scaffold demonstrating anti-inflammatory, antioxidant, and antiproliferative properties in diverse preclinical models. Recent investigations reveal that ESC modulates critical signaling pathways, including NF-κB, Nrf2/antioxidant response element (ARE), and mitochondrial apoptotic cascades, across multiple disease contexts encompassing dermatology, metabolic disorders, cardiovascular disease, neurodegeneration, hepatorenal protection, and malignant transformation. Structural modification of the coumarin ring system yields derivatives with enhanced target selectivity and improved metabolic stability in select compounds. However, ESC is substantially limited by poor aqueous solubility, rapid phase II metabolism, and an estimated low oral bioavailability (5-15%), representing a critical barrier to therapeutic translation. Notably, no phase II/III clinical trials have been completed, and human safety and efficacy data remain virtually absent. Recent innovations, including cocrystal technology, nanoparticle formulations, and rational structural optimization, demonstrate promise in preclinical contexts. This comprehensive review synthesizes pharmacological evidence across disease indications, evaluates bioavailability enhancement strategies, explicitly discusses evidence limitations, addresses safety considerations, and outlines translational research priorities essential for clinical or nutraceutical development.