Diosmetin as a Promising Anticancer Agent: Mechanisms, Structural Optimization, and Advanced Delivery Systems

Abstract

Diosmetin (Dio) is a natural flavonoid with broad-spectrum anticancer activity against various malignancies through mechanisms involving cell cycle arrest, apoptosis induction, metastasis inhibition, and modulation of oncogenic signaling pathways such as STAT3/c-Myc and PI3K/AKT/mTOR; with the exception of CDK2, which has been proposed as a direct target in esophageal squamous cell carcinoma, no other direct molecular targets of diosmetin have been identified to date. It also exhibits synergistic efficacy with reduced toxicity when combined with radiotherapy or chemotherapy. However, clinical translation is severely hampered by poor water solubility, low bioavailability, and unidentified direct molecular targets. Structural modifications (esterification, etherification, phosphorylation) and advanced drug delivery systems (SMEDDS, targeted liposomes, composite nanoparticles) offer promising strategies to overcome these limitations. This review provides an integrated framework covering the complete chain from extraction and chemical derivatization to formulation strategies and anticancer mechanisms, with critical analysis of current translational bottlenecks, particularly the disconnect between in vitro and in vivo findings. By integrating chemical optimization with pharmacological mechanisms, this review aims to provide a theoretical foundation to inform and guide future preclinical and translational research on Dio as a potential adjunct to existing cancer therapies. While some of these strategies have been validated in cancer models, others have been demonstrated in noncancer settings and await translation to oncology.