Ferroptosis-mediated metabolic reprogramming as a driver of the inflammatory microenvironment in neutrophilic asthma: a perspective.

Neutrophilic asthma is a severe asthma subtype marked by persistent airway neutrophilia, Th17-skewed inflammation, and poor responsiveness to glucocorticoids. The mechanisms driving chronic neutrophilic inflammation and corticosteroid resistance remain incompletely understood. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance. Emerging evidence suggests that ferroptosis is closely linked to cellular metabolism and immune regulation in inflammatory diseases. In this perspective article, we propose a hypothesis-generating framework in which ferroptosis-associated metabolic dysregulation may contribute to the development and persistence of neutrophilic asthma. Specifically, increased acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated phospholipid remodeling, enhanced fatty acid oxidation, nicotinamide adenine dinucleotide phosphate (NADPH) depletion, glutathione exhaustion, impaired glutathione peroxidase 4 (GPX4) function, and lipid peroxide amplification may collectively heighten neutrophil susceptibility to ferroptosis. We further propose a self-amplifying "ferroptotic relay," whereby ferroptotic neutrophils release oxidized lipid mediators and damage-associated molecular patterns (DAMPs) that drive inflammatory amplification, adaptive immune modulation, and sustained neutrophil recruitment within the airway microenvironment. We also examine how this ferroptosis-metabolism axis may contribute to chronic airway inflammation, glucocorticoid resistance, and disease heterogeneity. Finally, we highlight potential therapeutic opportunities involving ferroptosis-targeting agents, metabolic interventions, and biomarker-guided patient stratification. Although direct evidence for neutrophil ferroptosis in human neutrophilic asthma is still lacking, this framework may offer a conceptual foundation for future mechanistic, translational, and clinical investigations.