Trichosanthes kirilowii extract alleviated liver fibrosis and acute myocardial infarction by inhibiting VCAN to restrain monocyte senescence: Insights from bioinformatic analyses and experimental validation.

Abstract

BACKGROUND: Liver fibrosis and acute myocardial infarction (AMI) tended to co-occur. Cellular senescence and an imbalanced immune microenvironment were reported to serve as shared pathological hallmarks. However, the key driver genes remained unelucidated and lacked common therapies. The traditional Chinese medicine Gualou (Trichosanthes kirilowii, TK) used for related symptoms, hinted at a dual-organ protective role, but its mechanism was unestablished. METHODS: This study integrated bioinformatics analyses with experimental validation. First, differential-expression analysis, weighted gene co-expression network analysis and machine-learning algorithms were applied to publicly available transcriptomic datasets of liver fibrosis and AMI to identity hub genes. Subsequent immune infiltration analysis revealed immunological correlations between the two conditions. Single-cell RNA-seq data were interrogated to pinpoint a key gene. The coremine database was utilized to identify traditional Chinese medicines. In vivo, CCl₄-induced liver fibrosis and left-anterior-descending coronary-ligation-induced AMI mouse models were established. Low-, medium- and high-dose TK extract were administered orally. Interventions were assessed using histopathological staining, Western blot, ELISA, and flow cytometry to evaluate organ function, pathological changes, infarct size, fibrosis degree, inflammatory infiltration, and cellular senescence. RESULTS: Versican (VCAN) was identified as a key shared gene; its expression level correlated strongly with monocyte senescence signatures. In vivo experiments demonstrated that TK extract markedly ameliorated liver fibrosis and improved cardiac function, while simultaneously down-regulating VCAN expression. Mechanistic investigations revealed that TK extract, via VCAN suppression, modulated the senescence-associated secretory phenotype and decreased canonical senescence markers, thereby retarding monocyte senescence and concomitantly attenuating tissue injury and fibrotic deposition in both liver and heart. CONCLUSION: TK exerts bifunctional protection against liver fibrosis and AMI by targeting VCAN-mediated monocyte senescence.