{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:23Z","timestamp":1790920523848,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Chronic heart failure (CHF) is a systemic cardiovascular disease characterized by an extremely poor prognosis. Luteolin demonstrates promising therapeutic potential in the prevention and management of CHF. This study aims to explore the mechanism by which luteolin ameliorates CHF through mitigating mitochondrial damage and inhibiting cardiomyocyte apoptosis, using bioinformatics analysis combined with\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Network pharmacology was employed to identify functional targets of luteolin, as well as target genes associated with CHF and mitochondrial damage. The overlapping targets from the three datasets were obtained to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, followed by molecular docking, were then conducted. Bioinformatic approaches were utilized to screen potential signature genes from the PPI network to build a clinical prediction model. 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\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u2013M\u2013C 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.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , luteolin markedly downregulated L-M-C genes (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05) and attenuated doxorubicin-induced cardiomyocyte injury.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , in CHF rats, luteolin reduced myocardial L-M-C gene expression (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), ameliorated myocardial lesions, and suppressed fibrosis and cardiomyocyte apoptosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1977166","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:35:21Z","timestamp":1790919321000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of luteolin in treating chronic heart failure by regulating HIF-1 signaling pathway-mediated mitochondrial damage to inhibit cardiomyocyte apoptosis"],"prefix":"10.3389","volume":"14","author":[{"given":"Weiqi","family":"Shi","sequence":"first","affiliation":[{"name":"The First College of Clinical Medicine, Guangxi University of Chinese Medicine","place":["Nanning, Guangxi, 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