Natural compound 44DiOMEA alleviates cardiac fibrosis via targeting GIPC1 TGFBR3 axis to suppress Smad2/3 and PI3K/AKT signaling pathways
In our previous study, we found that GIPC1 and TGFBR3 mediated the anticardiac fibrotic effects of 44DiOMEA, a natural lipophilic ellagic acid derivative. So we performed RNAseq on TGFB1 induced human cardiac fibroblasts with or without 44DiOMEA treatment to delineate downstream signaling pathways. Among the genes modulated by TGFB1, the expression of 478 genes was significantly reversed by 44DiOMEA treatment. Key genes associated with fibroblast activation and fibrotic responses, including ACTC1, COL4A3, LTBP2, MFAP5, and IGFBP3, as well as genes encoding matricellular proteins, such as ELN, POSTN, CNN2, MMP8 and COMP, were highly upregulated in TGFB1 treated CFs compared to controls. Notably, these TGFB1induced fibrotic responses were markedly attenuated by 44DiOMEA treatment. In line with our snRNAseq data, GIPC1 mRNA levels remained unchanged, whereas TGFBR3 expression was downregulated by TGFB1 and restored by 44DiOMEA, suggesting the therapeutic potential of the compound. KEGG pathway enrichment analysis revealed that differentially expressed genes were significantly enriched in pathways critical to fibrosis, including ECM receptor interaction, focal adhesion, AGE RAGE signaling, PI3K Akt signaling, and TGFB signaling.