Necroptosis in Lung Diseases: Mechanism and Therapeutic Prospects

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD) are major pulmonary disorders that affect hundreds of millions worldwide and are leading causes of respiratory morbidity and mortality. Across these devastating diseases, necroptosis has emerged as a central pathogenic driver. This regulated lytic cell death pathway, executed via the receptor-interacting protein kinase 3 (RIPK3) and the terminal effector mixed lineage kinase domain-like protein (MLKL) signaling axis, promotes alveolar-capillary barrier disruption, sustained inflammation, and progressive fibrotic remodeling. Although inhibitors targeting RIPK1, RIPK3, and MLKL show promise in preclinical models, clinical translation is hindered by limited efficacy and safety concerns. Future breakthroughs require multidimensional strategies in drug development: enhancing precision at functional, molecular, and cellular levels (e.g., uncoupling kinase activity from scaffold function, conformation-guided design, nanoenabled delivery); advancing human-relevant preclinical models; exploring more specific targets; and developing combination therapies within the PANoptosis framework.