Homoisoflavonoids—From Natural Specificity and Biosynthesis to Precision Health‐Promoting Mechanisms

ABSTRACT Flavonoids are key natural health supplements and nutrients, renowned for their various physiological activities, including antioxidant, antibacterial, and anti‐aging effects. Homoisoflavonoids are a rare flavonoid subclass distinguished by an extended carbon bridge between the B‐ and C‐rings, forming a unique bi‐aromatic oxygen‐heterocyclic system. Homoisoflavonoids exhibit potent anti‐inflammatory, hypoglycemic, and anticancer activities. Notably, sappanone A potently mitigates neuroinflammation via the allosteric inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2), a mechanism recognized among the Top Ten Medical Advances in China (2017). Regarding hypoglycemic activity, brazilin exhibits superior in vivo potency at a lower dose (40 mg/kg) compared to conventional flavonoids (100 mg/kg). 4′,5,7‐Trihydroxy‐6,8‐dimethylhomoisoflavanone inhibits colorectal cancer (CRC) cell growth (half maximal inhibitory concentration, IC 50 = 4.6–6.7 µM), significantly suppressing xenograft tumor growth without systemic toxicity. This review systematically elucidates the unique structure–activity relationship (SAR) mechanisms of homoisoflavonoids in anti‐inflammatory, hypoglycemic, and anticancer activities. It underscores their distinctive natural distribution, defined by limited species ranges, strong tissue specificity, and convergent evolution. Furthermore, a potential biosynthetic pathway for homoisoflavonoids is proposed. This review synthesizes current knowledge to offer strategic insights and future directions for the precision breeding, targeted biosynthesis, and high‐value utilization of superior homoisoflavonoid germplasms.