Table 1_Mechanism of luteolin in treating chronic heart failure by regulating HIF-1 signaling pathway-mediated mitochondrial damage to inhibit cardiomyocyte apoptosis.docx

Single-cell transcriptomics (scRNA-seq) was performed to characterize the expression profiles of these signature genes in cardiomyocyte subpopulations. Lastly, the results were comprehensively validated by in vitro and in vivo experiments.</p>Results<p>In total, 329 overlapping targets of luteolin, mitochondrial damage and CHF were obtained; 122 core targets with above-average degree values were mainly enriched in the HIF-1 pathway.

Six signature genes (HIF1A, NOS2, BNIP3, BNIP3L, PDK1, and BBC3; collectively termed the L–M–C gene set) were identified through 113 machine-learning combinations. The six-gene clinical model demonstrated favorable predictive performance. scRNA-seq demonstrated progressive upregulation of L-M-C genes during the transition from normal to injured cardiomyocytes in CHF. In vitro, luteolin markedly downregulated L-M-C genes (P < 0.05) and attenuated doxorubicin-induced cardiomyocyte injury.

In vivo, in CHF rats, luteolin reduced myocardial L-M-C gene expression (P < 0.05), ameliorated myocardial lesions, and suppressed fibrosis and cardiomyocyte apoptosis.</p>Conclusion<p>Luteolin exerts therapeutic effects against CHF by inhibiting the HIF-1 signaling pathway and downregulating the expression of target genes such as NOS2 and BNIP3. This regulatory action attenuates myocardial mitochondrial damage and fibrosis, thereby ameliorating the pathological structural remodeling of the myocardium.</p>