A Circular Network of Coregulated L-Threonine and L-Tryptophan Metabolism Dictates Acute Lower Limb Ischemic Injury.

Abstract

Lower limb ischemia is characterized by reduced arterial perfusion in the lower limbs, leading to tissue ischemia and cell death. It is primarily caused by thrombosis and the rupture of arterial plaques, resulting in damage to ischemic muscle tissues. Metabolic processes are crucial in its development. Herein we combined single-cell data with metabolomics data to explore the pathways and mechanisms influencing lower limb ischemia. We analyzed single-cell and metabolomics data. In single-cell analysis, we identified different cell subpopulations and key regulatory genes, and biological enrichment analysis was performed to understand their functions and relationships. For metabolomics, mass spectrometry and chromatography techniques were employed to analyze metabolites in clinical samples. We performed differential analysis, correlation analysis, and Mendelian randomization to determine the relationships between key metabolites and genes. Nebl, Dapl1, Igfbp4, Lef1, Klrd1, Ciita, Il17f, Cd8b1, Il17a, Cd180, Il17re, Trim7, and Slc6a19 were identified to play a crucial role in lower limb ischemia. Important metabolites included L-threonine and L-tryptophan. The metabolism of L-threonine and L-tryptophan is linked to lower limb ischemia and thrombosis. B0AT1, encoded by SLC6A19, is closely related to these metabolites and appears to play a key role in lower limb ischemia development. Our analysis revealed the roles of key genes and metabolites in lower limb ischemia. These findings enhance our understanding of the pathogenesis of lower limb ischemia and provide new insights into its prevention and treatment.