H3K18 lactylation-hexokinase 2 positive feedback loop promotes osteogenesis of ASPCs in facial infiltrating lipomatosis.

BACKGROUND

Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by adipose hyperplasia and osseous overgrowth, driven by somatic PIK3CA mutations. While PIK3CA-induced metabolic reprogramming elevates lactate levels, the role of histone lactylation in FIL pathogenesis remains unclear.

METHODS

Adipose stem and progenitor cells (ASPCs) from FIL adipose tissue were isolated. Glycolysis inhibitors (2-DG, oxamate), lactate supplementation, and siRNA-mediated knockdown were used to modulate lactylation. CUT&Tag sequencing, Western blot, qPCR, ChIP-qPCR and functional assays (osteogenic/adipogenic differentiation) were performed to elucidate the potential mechanism.

RESULTS

FIL-ASPCs exhibited hyperlactylation, particularly at H3K18. H3K18la promoted osteogenesis by activating osteogenic genes, while adipogenesis remained unaffected. Inhibition of lactylation via glycolysis inhibitors or LDHA/LDHB knockdown suppressed osteogenic differentiation, whereas lactate supplementation reversed these effects. TGF-β1 stimulation could increase lactylation levels and promote osteogenic differentiation. Moreover, H3K18la upregulated hexokinase 2 (HK2), enhancing glycolysis and lactate production, thereby forming a lactate-H3K18la-HK2 positive feedback loop.

CONCLUSIONS

This study identified H3K18 lactylation as a key epigenetic driver of FIL-associated osseous hyperplasia via a lactate-H3K18la-HK2 feedback loop. Targeting this axis may offer therapeutic potential for FIL and related metabolic bone disorders.