Targeted structural destabilization of flavonoids: A novel paradigm for metabolic reprogramming and anti-senescence to repair the alveolar-capillary barrier.

Persistent disruption of the alveolar-capillary barrier (ACB) is the core pathological basis of acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). ACB deterioration reflects a complex pathological process involving macrophage immunometabolic reprogramming, epithelial stress responses, and senescence-associated impairment of alveolar repair. Traditional single-target anti-inflammatory strategies are difficult to reverse this microenvironmental deterioration. Based on evidence from literature mining, network pharmacology, molecular docking, molecular dynamics (MD) simulations, protein conformational biology, and structure-activity considerations, this paper proposes selected flavonoid compounds as candidate "Targeted Structural Destabilizers." Rather than representing a universal class effect of all flavonoids, this hypothesis applies to structurally compatible compounds whose scaffold features, hydroxylation patterns, and target-interface compatibility may permit conformational perturbation of pathogenic hub proteins such as TP53 and STAT3. These compounds are hypothesized to shift selected hub proteins toward more flexible, partially destabilized, or molten globule-like conformational states, thereby attenuating pathological signaling outputs in a compound- and target-context-dependent manner. Functionally, this proposed mechanism may contribute to ACB repair by suppressing HIF-1/STAT3-associated inflammatory glycolysis in macrophages, supporting metabolic restoration, and modulating TP53-associated senescence-associated secretory phenotype (SASP) programs in alveolar epithelial cells. This review outlines a hypothesis-driven framework linking targeted structural destabilization, metabolic reprogramming, and anti-senescence repair. Direct biophysical, cellular, and disease-model validation will be required to determine whether this proposed flavonoid-based paradigm can be translated into effective ACB repair strategies.