SCM-198 ameliorates pulmonary arterial hypertension by modulating gut microbiota in rats

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling and inflammation. This study aimed to investigate the therapeutic effects of SCM-198 (Leonurine) on monocrotaline (MCT)-induced PAH and its role in modulating gut microbiota composition and vascular signaling pathways.

A rat model of PAH was established via one-time intraperitoneal injection of MCT (50 mg/kg), followed by SCM-198 treatment (50 and 100 mg/kg) for 3 weeks. Pulmonary vascular remodeling was assessed by histological and morphometric analyses. 16S rRNA sequencing was performed to evaluate gut microbiota diversity and composition. Network pharmacology analysis was conducted to identify SCM-198 targets, including overlapping targets related to PAH, and to explore relevant signaling pathways via protein-protein interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

SCM-198 treatment significantly attenuated pulmonary arterial wall thickening and vascular remodeling. Microbial diversity exhibited a trend toward restoration, with increased abundance of Bacteroidota and unclassified_Muribaculaceae, and decreased levels of Clostridium_sensu_stricto_1 and Allobaculum. Linear discriminant analysis effect size (LEfSe) analysis identified distinct microbial signatures indicative of anti-inflammatory shifts. Network pharmacology identified 71 overlapping targets between SCM-198 and PAH, including Akt1 and Mmp9, enriched in PI3K-Akt signaling, oxidative stress, and inflammatory pathways.

These findings suggest that SCM-198 exerts therapeutic effects in PAH through combined gut microbiota modulation and multi-target regulation of vascular signaling networks, offering new insights into adjunctive strategies for PAH treatment.