Human Neutrophil Elastase and the Protein-Storm Axis: Reversible Synthetic Inhibitors in Inflammatory Disease.

Human neutrophil elastase (HNE) is a central mediator of neutrophil-driven inflammation. Yet, despite decades of research and drug development, therapies targeting HNE have not consistently translated into clear clinical benefits. We suggest that this translational gap partly arises from how HNE has traditionally been conceptualized, as a single enzyme to inhibit. In biological systems, however, HNE operates within a complex and tightly regulated network of proteases and inflammatory mediators. This network is spatially compartmentalized and strongly influenced by local redox conditions, making HNE activity highly context-dependent. From a systems perspective, HNE acts as an amplifier of inflammation. Its extracellular activity connects several pathological processes, including activation of innate immunity, extracellular matrix degradation, disruption of epithelial and endothelial barriers, and the transition toward chronic inflammation. In this review, we integrate insights from enzymology, systems biology, and clinical research to reassess the development of HNE inhibitors, ranging from endogenous antiproteases to more recent reversible synthetic compounds. Despite their chemical and pharmacological diversity, many of these strategies have encountered similar limitations. We therefore argue that future therapeutic approaches should move beyond the inhibition of HNE as an isolated target and instead aim to modulate the broader protease network, with particular attention to drug-target kinetics and precise delivery to disease-relevant microenvironments.