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

Versican (VCAN) was identified as a key shared hub gene in both liver fibrosis and acute myocardial infarction through integrated bioinformatics analyses.

• Differential-expression analysis, weighted gene co-expression network analysis (WGCNA), and machine-learning algorithms were applied to publicly available transcriptomic datasets of liver fibrosis and AMI.
• Single-cell RNA-seq data were interrogated to pinpoint VCAN as the key gene.
• VCAN expression level correlated strongly with monocyte senescence signatures.
• The coremine database was utilized to identify Trichosanthes kirilowii (TK) as a traditional Chinese medicine associated with these conditions.

Immune infiltration analysis revealed immunological correlations between liver fibrosis and AMI, with monocyte senescence identified as a shared pathological hallmark.

• Cellular senescence and an imbalanced immune microenvironment were reported as shared pathological hallmarks of both conditions.
• Monocyte senescence signatures were strongly correlated with VCAN expression levels in both disease contexts.
• The senescence-associated secretory phenotype (SASP) was implicated as a mechanistic link between VCAN expression and tissue injury.

TK extract markedly ameliorated liver fibrosis in CCl4-induced mouse models.

• CCl4-induced liver fibrosis mouse models were established and treated with low-, medium-, and high-dose TK extract administered orally.
• Interventions were assessed using histopathological staining, Western blot, ELISA, and flow cytometry.
• TK extract reduced fibrosis degree and inflammatory infiltration in liver tissue.
• TK extract down-regulated VCAN expression in liver tissue.
• TK extract decreased canonical senescence markers and modulated the senescence-associated secretory phenotype in liver tissue.

TK extract improved cardiac function and reduced infarct size in left-anterior-descending coronary-ligation-induced AMI mouse models.

• Left-anterior-descending coronary-ligation-induced AMI mouse models were established and treated with low-, medium-, and high-dose TK extract administered orally.
• TK extract improved organ function, reduced infarct size, and attenuated fibrotic deposition in cardiac tissue.
• TK extract down-regulated VCAN expression in cardiac tissue.
• Histopathological staining, Western blot, ELISA, and flow cytometry were used to assess pathological changes and cardiac function.

TK extract retarded monocyte senescence in both liver fibrosis and AMI models through VCAN suppression.

• TK extract, via VCAN suppression, modulated the senescence-associated secretory phenotype (SASP).
• TK extract decreased canonical senescence markers as assessed by flow cytometry and Western blot.
• Monocyte senescence was retarded concomitantly with attenuation of tissue injury and fibrotic deposition in both liver and heart.
• The mechanism was consistent across both organ disease models, suggesting a shared VCAN-mediated pathway.