Abstract
<title>Abstract</title> <p>Idiopathic pulmonary fibrosis (IPF) features progressive extracellular matrix deposition and lung scarring driven by fibroblast-to-myofibroblast transition (FMT). A synergistic interplay between metabolic reprogramming and the hypoxic microenvironment is pivotal. Hypoxia-inducible factor-1α (HIF-1α) orchestrates a glycolytic shift, supporting myofibroblast activation and amplifying profibrotic signaling, including transforming growth factor-β (TGF-β). This induces a feed-forward loop where glycolytic flux produces lactate, which further stabilizes HIF-1α and fuels fibrosis. Lactate also mediates histone lactylation, an epigenetic modification promoting pro-fibrotic gene expression. This study investigated the effect of baicalein in bleomycin-induced IPF and it significantly alleviated lung fibrosis. Mechanistically, FHL2 is upregulated and forms phase-separated condensates with HIF-1α within myofibroblast nuclei in IPF. These condensates promote the expression of glycolytic and fibrotic genes. Baicalein disrupts the assembly of the HIF-1α/FHL2 complex and inhibits its phase separation, thereby suppressing the glycolytic pathway. As a result, baicalein decreases lactate production and reduces subsequent histone H3K18 lactylation at pro-fibrotic gene promoters. In conclusion, baicalein ameliorates IPF by dual regulation: inhibiting the HIF-1α/FHL2 phase-separated transcriptional hub to suppress metabolic reprogramming and reducing lactate-derived histone lactylation. This reveals a novel mechanism targeting the metabolism-epigenetics axis in IPF.</p>