Abstract
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening cytokine storm syndrome caused by immune hyperactivation. Given the pivotal role of the JAK/STAT pathway in HLH pathogenesis, JAK inhibition represents a potential therapeutic strategy.
Methods: We evaluated the highly selective JAK1 inhibitor golidocitinib and JAK1/2/3/TYK2 inhibitor gecacitinib in both primary (LCMV-infected perforin-deficient, Prf1−/−) and secondary (CpG-induced) mouse models of HLH. Vehicles and the JAK1/2 inhibitor ruxolitinib served as negative and positive controls, respectively.
Results: Both golidocitinib and gecacitinib were safe and well-tolerated in primary (pHLH) and secondary (sHLH) models. Golidocitinib demonstrated superior efficacy, significantly improving clinical manifestations including hepatosplenomegaly, hemoglobin, counts of red blood cells, white blood cells, platelets and neutrophils, liver function parameters and reduced serum levels of cytokines (TNFα, IFNγ, IL-10, etc.). In sHLH, gecacitinib and ruxolitinib only alleviated hepatosplenomegaly and erythropenia; in pHLH, these agents solely improved erythropenia and liver function. Critically, golidocitinib significantly outperformed gecacitinib and ruxolitinib in resolving hepatosplenomegaly and pancytopenia across both HLH models. Flow cytometry for splenocytes revealed marked decreases in CD80+ neutrophils and monocytes following golidocitinib treatment in sHLH; whereas in pHLH, its exceptional efficacy correlated with CD8+ T cell modulation, markedly suppressing TNFα/IFNγ production upon LCMV gp33-41 stimulation.
Conclusion: Golidocitinib and gecacitinib demonstrate favorable preclinical tolerability and efficacy in HLH. The highly selective JAK1 inhibitor golidocitinib exhibits broadly superior therapeutic effects to gecacitinib and ruxolitinib in both HLH subtypes.
