Isoquercitrin: From natural source to clinical candidate - Synthesis, pharmacology, and metabolic safety

Isoquercitrin (ISQ, C₂₁H₂₀O₁₂) is a typical flavonoid compound characterized by a C6-C3-C6 backbone structure. It is widely distributed across various plant families, including Fabaceae, Poaceae, and Solanaceae, and can be obtained through standardized extraction processes. Modern pharmacological studies have demonstrated that ISQ exhibits extensive pharmacological activities and exerts significant therapeutic effects on diseases affecting the circulatory, nervous, metabolic, and musculoskeletal systems. In this review, a systematic literature search was conducted using the Web of Science, Google Scholar, ScienceDirect, and PubMed databases for publications from 2015 to the present. Based on predefined inclusion criteria, 1694 articles were screened, and 117 studies were ultimately included for systematic analysis. This study comprehensively evaluates the pharmacological mechanisms, toxicity, synthetic methods, and pharmacokinetic properties of ISQ. Several studies have shown that ISQ exerts its multifaceted biological effects through modulation of key biological processes. Mechanistically, ISQ regulates JAK/STAT3 signal transduction, activates the Nrf2/ARE antioxidant pathway, and suppresses NF-κB-mediated inflammatory responses. Furthermore, it concurrently modulates AMPK-mediated energy metabolism, PI3K/Akt-dependent cell survival, and Wnt-associated developmental pathways. These coordinated mechanisms collectively contribute to its anti-inflammatory, antioxidant, metabolic regulatory, and tumor-suppressive properties. The compound selectively induces programmed cell death in cancer cell lines such as A549, AGS, and Huh7 through a cell type-dependent cytotoxic mechanism. Analysis of the pharmacokinetic characteristics of ISQ has indicated low oral bioavailability, suggesting the necessity for formulation improvement. Additionally, this study explores potential research directions and the clinical translation pathways of ISQ. This review comprehensively summarizes the latest research advances in ISQ, encompassing its natural sources, synthetic approaches, pharmacological activities, metabolic pathways, and toxicological profiles.