Oxygen-Driven Thermal Degradation of Isorhamnetin in Boiling Water: Product Profiling, Energetics, and Antiobesity Mechanisms in <i>Caenorhabditis elegans</i>

Dietary flavonoids readily undergo structural transformations upon heating, and it remains unclear whether their postheat bioactivity is driven by the parent compounds or its degradation products. Here, we constructed a time-resolved three-dimensional product-structure-activity network of isorhamnetin (ISO) in boiling water. A total of 12 products were identified and classified as phenolic acids, hydroxylated adducts, and dimers. Density functional theory calculations supported a degradation mechanism involving quinone formation, hydroxide attack at the C2 position, and C-ring cleavage. Further biological evaluation revealed that ISO and its key degradation products, phloroglucinol and 2,4,6-trihydroxybenzoic acid, mitigated glucose-induced metabolic reprogramming, and lipid accumulation in <i>Caenorhabditis elegans</i> through a DAF-16/FOXO-dependent mechanism associated with H3K4me3/H3K27me3. Overall, this work presents a structural landscape of ISO under cooking-like conditions and provides new insight into the retention of bioactivity during the thermal transformation of polyphenols.