Research Information System
MEDICINA-LITHUANIA, vol.61, no.9, 2025 (SCI-Expanded, Scopus)
Background: The liver's role as a metabolic gatekeeper positions it uniquely to influence systemic metabolic homeostasis and potentially modulate leukemogenesis through hepato-hematopoietic crosstalk. Recent observations of rare hematological malignancies following mRNA vaccination warrant mechanistic investigation. Hypothesis: We propose that mRNA vaccines, through their preferential hepatic tropism via lipid nanoparticles (LNPs), may transiently dysregulate hepatic metabolism in susceptible individuals, creating metabolic perturbations that amplify pre-existing leukemogenic vulnerabilities through five interconnected mechanisms: (1) competitive folate sequestration for vaccine-induced lymphoproliferation, potentially starving bone marrow precursors of essential one-carbon units; (2) hepatic lipid processing overload from LNP accumulation, exacerbating phospholipid dysregulation in pre-leukemic clones; (3) cytokine-mediated upregulation of hepatic indoleamine 2,3-dioxygenase (IDO), accelerating tryptophan catabolism and creating an immunosuppressive milieu favoring leukemic escape; (4) inflammatory induction of hepcidin, sequestering hepatic iron while triggering compensatory intestinal iron hyperabsorption and potential bone marrow iron overload; and (5) increased hepatic NADPH demand for antioxidant defense and lipid metabolism, diverting reducing equivalents from bone marrow stromal support. Implications: This hypothesis suggests that transient hepatic metabolic perturbations may create a permissive milieu for leukemogenesis in metabolically vulnerable individuals. The proposed mechanisms generate testable predictions and identify potential therapeutic targets, including folate supplementation, IDO inhibition, and iron chelation in high-risk cohorts.