The multidimensional signaling of ELANE: from congenital hematopoietic failure to immune microenvironment crosstalk and targeted interventions

Mutations in the neutrophil elastase gene (ELANE) have classically been established as the primary genetic etiology of severe congenital neutropenia (SCN) and cyclic neutropenia (CyN), characterized by early-stage granulocytic maturation arrest and a predisposition to life-threatening infections. However, recent high-throughput transcriptomic, multi-omics, and functional studies have unveiled a paradigm-shifting, multidimensional role for neutrophil elastase (NE) that extends far beyond the confines of bone marrow failure. As a highly active serine protease, NE has emerged as a central hub in regulating recently discovered forms of regulated cell death (RCD), including pyroptosis, ferroptosis, and NETosis, and orchestrating the tumor immune microenvironment (TIME). Within the bone marrow, mutant NE triggers intense proteotoxic stress, reactive oxygen species (ROS) accumulation, and a unique proapoptotic "aggrephagy" (the selective autophagic degradation of misfolded protein aggregates), driving granulocyte colony-stimulating factor (G-CSF) resistance and clonal evolution toward acute myeloid leukemia (AML). Extracellularly, NE released via neutrophil extracellular traps (NETs) acts as a fascinating double-edged sword: it possesses the intrinsic capability to selectively eradicate genetically diverse cancer cells by cleaving the CD95 death domain and interacting with histone H1 isoforms, yet it concomitantly mediates immunosuppression, chemoresistance, and systemic inflammatory response syndrome (SIRS) in sepsis by reprogramming macrophage polarization. This review systematically synthesizes the intricate molecular mechanisms of NE, emphasizing the profound crosstalk between hematopoietic failure, inflammatory cell death pathways, and tumor immunology. Furthermore, this review highlights the translational potential of these discoveries, exploring cutting-edge therapeutic strategies, including CRISPR/Cas9-based precise base editing, dual-nickase promoter targeting, and selective allosteric small-molecule inhibitors, ultimately aiming to bridge the critical gaps from bench to bedside.