Long-distance trail running induces functional iron deficiency driven by inflammation

Iron is a critical cofactor for numerous cellular processes, particularly mitochondrial oxidative phosphorylation. Functional iron deficiency, often driven by inflammation-induced hepcidin upregulation, restricts iron availability to peripheral tissues despite adequate stores. Physical exertion elicits transient inflammation, but its impact on systemic iron trafficking and cellular iron sensing remains unclear. We analyzed serum and peripheral blood mononuclear cells (PBMCs) from 7 elite endurance athletes before and after the long-distance trail run of the World Mountain and Trail Running Championships 2023 (86.9 km, +6500 meters ascent, -6920 meters descent), conducted in Innsbruck, Austria. Systemic iron markers and PBMC gene expression were measured to characterize iron redistribution under extreme physiological stress. Extensive exercise induced increased interleukin-6 expression, paralleled by elevated hepcidin and ferritin levels, whereas serum iron and transferrin saturation declined, indicating inflammation-driven functional iron deficiency. Biochemical signs of intravascular hemolysis were also evident. At the cellular level, PBMCs displayed a transcriptional signature consistent with restricted iron availability: upregulation of hypoxia-inducible and iron uptake genes and downregulation of iron storage and export genes. These changes likely reflect both iron sequestration and hemolysis-related iron handling. Our findings demonstrate that long-distance trail running induces functional iron deficiency through inflammatory and hemolytic mechanisms, mirrored by adaptive changes in PBMC gene expression, particularly the upregulation of iron import and hypoxia genes. Alterations of iron homeostasis during extensive physical activity may affect mitochondrial activity and cellular metabolic functions.