Self-assembly of glycyrrhizic acid and aconitine alleviates heart failure by inhibiting autophagy and inducing reprogramming of energy metabolism
- Phytomedicine. 2026 Jun:155:158094. doi: 10.1016/j.phymed.2026.158094.
- 1. Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai 200240, China.
- 2. Shanghai Jiao Tong University, No.800 Dongchuan Road, Shanghai 200240, China. Electronic address: [email protected].
Background: Herb pairs are the fundamental basis of Traditional Chinese Medicine (TCM) prescriptions. The Aconitum carmichaelii Debx-Glycyrrhiza uralensis Fisch herb pair has superior anti-heart failure efficacy compared with the separate use of these two herbs. However, the active substances in this herb pair that protect against heart failure, and their interactions during decoction, are poorly understood.
Purpose: To elucidate how aconitine (A) and glycyrrhizic acid (G), the active substances in this herb pair, react during decoction and the mechanism by which the reaction products alleviate heart failure.
Methods: A and G were decocted and formed a self-assembled complex (GA). We characterized the structure of GA and investigated its self-assembly mechanism. An in vivo and in vitro heart failure model was employed to investigate the mechanism by which GA alleviated heart failure.
Results: The self-assembly of A and G was driven by electrostatic interaction, intermolecular hydrogen bonds, and the hydrophilic/hydrophobic effects. GA alleviated heart failure in vivo and in vitro by inhibiting the overactivation of the MAPK-ERK pathways, restoring calcium homeostasis, and activating the lipoic acid metabolism pathway. Valosin-containing protein was identified as the target protein of GA by DARTS assays, and GA was proven to inhibit Autophagy and prevent remodeling of mitochondria to inhibit Mitophagy. GA-induced reprogramming of energy metabolism ultimately decelerated the progression of heart failure.
Conclusion: We proposed that GA differs from G and A because only GA can bind the specific protein target and, by affecting different pathways, alleviate heart failure synergistically. Our research raised a new strategy for discovering the scientific explanation of TCM compatibility.