Abstract Background Sheng-Xian-Tang (SXT), a traditional Chinese medicine, ameliorates doxorubicin (DOX)-induced chronic heart failure (CHF), yet its molecular mechanisms remain elusive. Objective To elucidate SXT's cardioprotective mechanisms against DOX-induced CHF. Methods In vivo, cardioprotection was evaluated via echocardiography, oxidative stress assays, and histopathology. Integrated metabolomic and 16S rRNA sequencing identified metabolic disruptions. Serum pharmacochemistry analysis identified hepatic bioactive compounds targeting phenylalanine hydroxylase (PAH). Molecular docking, CETSA, SPR, and enzyme activity assay validated neomangiferin-PAH interactions. Results SXT dose-dependently improved DOX-induced cardiac dysfunction in rats. Metabolomic and microbiome analyses confirmed phenylalanine metabolic disorder in the CHF rats. DOX exposure elevated phenylalanine levels in plasma, urine, and heart, reducing hepatic PAH expression and function while inducing ectopic phenylalanine catabolism in the heart. Phenylalanine administration exacerbated the cardiac abnormalities, whereas SXT effectively prevented attenuated DOX-induced cardiac toxicity. CETSA and SPR revealed a strong binding of neomangiferin to PAH, stabilizing its interaction with cofactor BH 4 and preventing DOX-induced PAH inhibition. Conclusions SXT mitigated DOX-induced CHF through hepatic PAH modulation. Neomangiferin could enhance PAH stability via competitive binding. Targeting PAH-phenylalanine metabolism emerged as a novel therapeutic strategy for DOX-induced cardiac dysfunction. Graphical Abstract
Pang et al. (Mon,) studied this question.