Acute exercise shifts inferred immune cell composition and cytotoxic gene programs in pediatric sickle cell anemia

This study characterizes the acute exercise-induced remodeling of the whole-blood transcriptome and inferred immune microenvironment in pediatric and adolescent patients with sickle cell anemia (SCA). By integrating transcriptomic profiling (GEO: GSE244401) with immune cell deconvolution and multi-level regulatory network analyses, we systematically dissected the molecular response to an acute interval exercise challenge. We identified 107 differentially expressed genes (89 upregulated, 18 downregulated) primarily enriched in natural killer (NK) cell cytotoxicity, T cell activation, and antigen presentation pathways. Protein-protein interaction (PPI) network analysis highlighted 16 hub genes (e.g., GZMB, PRF1, NKG7), whose upregulation significantly correlated with an increased inferred abundance of circulating NK cells and CD8 + T cells, alongside a concomitant reduction in neutrophils and eosinophils. Furthermore, regulatory network analysis implicated master transcription factors (e.g., EZH2, GLIS2) and key miRNAs (e.g., miR-21-5p, miR-130b-3p) in coordinating these acute cytotoxic responses through target genes such as TGFBR3 and FASLG. In conclusion, acute exercise triggers a rapid remodeling of the immune landscape, potentially attenuating granulocyte-driven inflammation while activating lymphocyte-mediated immunity. These findings reveal the complex "double-edged" transcriptional responses to exercise in pediatric SCA, providing a critical mechanistic foundation for developing individualized, safely monitored exercise prescriptions.

The online version contains supplementary material available at 10.1007/s13205-026-04922-9.