Serine synergizes with lipopolysaccharide to induce macrophage pyroptosis through extracellular Hsp90α and early skin immune microenvironment disruption in diabetic foot.

BACKGROUND: The pathogenesis of early-stage skin lesions in diabetic foot (DF) remains poorly understood, and cannot be fully explained by conventional theories. Skin microbiota dysbiosis has recently emerged as a critical factor, but the underlying mechanisms remain unclear. METHODS: In this study, we integrated metabolomics and metagenomics analyses of skin samples to investigate metabolic dysregulation driven by microbial dysbiosis. RESULTS: We identified elevated serine as a key metabolic alteration strongly correlated with a dysbiotic microbiota structure. Functionally, we demonstrate that abnormal serine accumulation contributes to the dysregulation of the early skin immune microenvironment in the diabetic foot. Mechanistically, our results reveal that excess serine synergizes with lipopolysaccharide (LPS) to stimulate the release of eHsp90α from keratinocytes, which was strictly dependent on the Akt/mTOR/HIF-1α pathway. This released eHsp90α then acts as a damage-associated molecular pattern, promoting both the migration and subsequent pyroptotic cell death of macrophages. CONCLUSIONS: Collectively, our findings suggest a novel pathogenic axis where a microbiota-host derived metabolite collaborates with a bacterial endotoxin to promote inflammatory cell death, which is closely associated with early skin lesions in DF. This work not only elucidates a new mechanism for DF pathogenesis but also suggests that the serine-eHsp90α-pyroptosis axis may serve as a potential candidate for future therapeutic exploration.