Quercetagetin phospholipid complex self-microemulsifying delivery system for enhanced oral delivery and alcoholic liver injury protection.

Alcoholic liver disease (ALD), a major diet-related public health concern, underscores the need for effective nutritional interventions derived from edible bioresources. Quercetagetin (QG), a potent polyphenolic flavonoid abundantly found in marigolds (Tagetes erecta L.)-a plant traditionally consumed as a health-promoting herbal tea and a recognized source of the nutraceutical lutein-holds great promise for liver protection. However, its poor aqueous solubility and low oral bioavailability severely limit its application in food and nutraceutical formulations. Herein, a QG-loaded phospholipid complex self-microemulsifying delivery system (QGPC-SMEDS) was designed and optimized utilizing pseudo-ternary phase diagrams and a D-optimal mixture design, the optimized QGPC-SMEDS formulation was comprehensively characterized. It showed 4.62-fold higher permeability in Caco-2 cells and 2.55-fold greater oral bioavailability in rats versus unformulated QG. Consequently, in vivo pharmacodynamic evaluation in mice demonstrated that QGPC-SMEDS exhibited superior protective efficacy against ALD compared to free unformulated QG. Integrated analysis of metabolomic and transcriptomic data revealed that ethanol exposure induces the expression of Gm43096 and Pla2g4f, resulting in elevated levels of D-erythro-sphingosine. This upregulation activates the necroptosis pathway, contributing to the development of acute liver injury. In contrast, both QG and QGPCS treatments downregulate the expression of Gm43096 and Pla2g4f, thereby reducing the production of D-erythro-sphingosine and suppressing necroptosis. Collectively, this study not only presents therapeutically effective nanoplatform for ALD but also provides a scientifically grounded strategy for the efficient delivery of food-derived polyphenols, contributing directly to the fields of functional food development and nutraceutical science.