A novel SLC2A10 gain-of-function variant links glycolytic macrophage polarization to chronic nonbacterial osteomyelitis

Chronic nonbacterial osteomyelitis is a rare autoinflammatory bone disorder with unclear etiology. In a Chinese family, whole-exome sequencing identified a heterozygous missense variant in SLC2A10 that cosegregated with disease. Structural modeling suggested that the substitution disrupts hydrogen bond within the transmembrane domain, potentially altering glucose transport activity. In vitro, the expression of the p.Asp292Glu variant in macrophages enhanced glucose uptake, increased glycolytic activity, and promoted pro-inflammatory polarization, accompanied by increased production of inflammatory mediators. The variant also accelerated osteoclast differentiation and suppressed osteoblast-mediated mineralization, indicating a disruption of bone homeostasis. Zebrafish expressing the p.Asp292Glu variant exhibited enhanced inflammatory responses, increased reactive oxygen species accumulation, elevated macrophage infiltration in the mandibular region, and impaired bone mineralization. Transcriptomic analysis confirmed activation of glycolytic and inflammatory signaling pathways, as well as enrichment of osteoclast differentiation networks. These findings demonstrate that the SLC2A10 variant exerts a gain-of-function effect driving glycolysis-dependent macrophage polarization and osteoclastogenesis, leading to chronic inflammatory bone destruction. This study broadens the genetic understanding of chronic nonbacterial osteomyelitis and suggests a potential therapeutic target.