Integrating Network Pharmacology and In Vitro 3D Cardiac Organoid Model Validation to Investigate the Action Mechanism of Shenfu Xiangshao Decoction on Heart Failure

ABSTRACT: Heart failure (HF) represents a significant global public health challenge with profound implications for human health. Shenfu Xiangshao Decoction (SFXSD) is a commonly used adjuvant therapy for HF. However, its molecular mechanism remains unclear. This study aims to explore the core components, key targets, and potential mechanisms of SFXSD in the treatment of HF. Network pharmacology, molecular docking, and molecular dynamics simulations were used to identify the active compounds and targets of SFXSD. A 3D HF cardiac organoid model was developed using doxorubicin (DOX). Techniques such as Western blotting, TUNEL staining, ELISA, and Masson staining were performed to investigate the mechanisms of SFXSD. SFXSD acted on HF, comprising 126 active ingredients and 33 core cross-targets. The 4 principal effector components, quercetin, kaempferol, licochalcone A, and naringenin, could form stable complexes with the core target MAPK14 (p38 MAPK). In this study, we successfully constructed an HF cardiac organoid model using 10 μM DOX, on which the mechanism was validated. The results indicated that quercetin and kaempferol, the active ingredients of SFXSD, could ameliorate DOX-induced cardiac organoids apoptosis, inflammation, and fibrosis by reducing the expression of p38/ERK MAPK, BAX/BCL-2 ratio, the release of TNF-α, and IL-6. This in vitro 3D cardiac organoid model provides a valuable platform for drug screening and disease modeling, while the discovery of quercetin and kaempferol offers a solid theoretical basis for HF treatment.