H3K18 histone lactylation mediates hypoxia-induced FBXW11 upregulation and supports proliferative and self-renewal-associated properties of hair follicle stem cells.

Hair follicle stem cells (HFSCs) reside in a relatively hypoxic niche and preferentially use glycolytic metabolism, but how metabolic adaptation is coupled to epigenetic regulation of HFSC function remains incompletely understood. Since oxidative phosphorylation produces more reactive oxygen species (ROS) than glycolysis, and excessive ROS production eliminates various stem cell properties including quiescence and self-renewal. Stem cells prefer glycolysis as their main energy source. Here, cultured human HFSCs were exposed to 2%O2. Hypoxia increased HIF-1α expression, glycolysis-related gene expression, intracellular H3K18 histone lactylation (H3K18la), EdU incorporation, colony-forming efficiency, and HFSC-associated markers CK15, CK19, and CD34 expression. Separate treatment with the glycolysis inhibitors 2-deoxy-D-glucose (2-DG) or oxamate reduced lactate accumulation, H3K18la, and HFSC-associated marker expression. Integrated H3K18la CUT&Tag and RNA sequencing identified 822 genes with concordantly increased H3K18la peaks and mRNA levels, with ubiquitin-mediated proteolysis among the enriched pathways. FBXW11 was prioritized as a candidate E3 ubiquitin ligase target. IGV visualization and H3K18la ChIP-qPCR showed increased H3K18la enrichment at the FBXW11 locus under hypoxia, whereas 2-DG or the p300 inhibitor C646 attenuated H3K18la enrichment and FBXW11 expression. FBXW11 overexpression increased EdU incorporation, colony formation, and HFSC-associated marker expression, while FBXW11 knockdown attenuated hypoxia-induced clonogenic growth and proliferation. In an ex vivo whole-hair-follicle culture model, hypoxia enhanced hair shaft elongation, and this effect was reduced by FBXW11 knockdown. Together, these findings support a hypoxia-glycolysis/lactate-H3K18la-FBXW11 pathway that contributes to proliferative and self-renewal-associated phenotypes of cultured HFSCs and to hypoxia-responsive hair shaft growth ex vivo. Further in vivo studies are required to establish its role in physiological hair cycle.