Mechanistic elucidation of Wuling Powder targeting macrophage polarization to ameliorate renal ischemia-reperfusion...

The blurry mechanism of Wuling Powder (WLP) in treating renal ischemia-reperfusion injury (R-IRI) has greatly hindered its clinical promotion and application as well as the development of modern preparations. This study applied computational systems pharmacology combined with experimental validation to reveal the mechanism of Wuling Powder (WLP) in ameliorating renal ischemia reperfusion injury (R-IRI) by regulating macrophage polarization (MP).

Firstly, the core target mechanism of WLP in treating R-IRI by regulating MP was clearly identified through using multidimensional AI computational systems pharmacology, including network pharmacology, the Gene Expression Omnibus database analysis, machine learning, molecular docking etc.

As a result, the core target of WLP in improving MP for treating R-IRI was confirmed to be PLAUR, HSPA1A, and FOS. Then, molecular dynamics simulation revealed that the 3,4-Dihydroxybenzaldehyde-PLAUR complex, which exhibited the least negative docking score, could still bind stably. On this basis, in vivo experiments combined with multivariate statistics and correlation analysis further demonstrated that WLP and its main active compound 3,4-Dihydroxybenzaldehyde could significantly modulate MP by regulating PLAUR to improve R-IRI.

These findings collectively support PLAUR, HSPA1A, and FOS as core therapeutic targets through which WLP modulates MP to alleviate R-IRI. This systematic research provides a solid theoretical basis for the clinical application and modern drug development of WLP in the prevention and treatment of R-IRI.