Stem cell research & therapy · 2025
H3K18 lactylation-hexokinase 2 positive feedback loop promotes osteogenesis of ASPCs in facial infiltrating lipomatosis.
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Chen Hongrui, Hua Chen, Chang Shih-Jen, Qiu Yajing, Lin Xiaoxi, Sun Bin
Аннотация
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.
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.