Necroptosis in asthma: a critical driver of immune dysregulation and airway remodeling

Asthma is a heterogeneous chronic airway disease traditionally framed within the context of dysregulated adaptive T helper 2 (Th2) immunity. However, this paradigm insufficiently explains disease chronicity, structural remodeling, and the limited efficacy of corticosteroids in specific endotypes. The discovery of necroptosis, a regulated form of lytic cell death governed by receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) and mixed-lineage kinase domain-like protein (MLKL), introduces a transformative perspective. This review posits that necroptosis is not a passive endpoint but an active pathogenic hub in asthma. We systematically dissect how asthma-relevant triggers (allergens, viruses, pollutants) activate necroptosis in a cell-specific manner. We detail the consequences: damage-associated molecular pattern (DAMP)-driven initiation and amplification of type 2 inflammation via epithelial death, the establishment of a neutrophilic, steroid-refractory milieu through immune cell necroptosis, and direct contributions to airway remodeling. Furthermore, we discuss the interconnectedness of necroptosis with pyroptosis and apoptosis within the PANoptosis framework, and acknowledge the limitations of current evidence derived largely from preclinical models. Finally, we explore therapeutic implications, advocating for patient stratification using necroptosis biomarkers and evaluating novel pharmacological inhibitors. By integrating necroptosis into the asthma pathophysiological network, this review provides a unified mechanistic framework that bridges initial insult to sustained inflammation and tissue remodeling, unveiling novel avenues for disease-modifying therapies.