Artesunate Alleviates Inflammatory Injury in Neonatal Acute Respiratory Distress Syndrome Through CCL5-Mediated Pyroptosis of M2 Macrophage Subsets.

Neonatal acute respiratory distress syndrome (NARDS) is a life-threatening respiratory disorder characterized by high mortality and significant long-term morbidity. Increasing evidence suggests that pyroptosis contributes to pulmonary tissue injury in ARDS. In this study, single-cell RNA sequencing (scRNA-seq) was utilized to investigate the molecular mechanisms underlying pyroptosis within the NARDS microenvironment. Our analysis identified chemokine (C-C motif) ligand (CCL5) expression in M2 macrophages as a potential regulator of pyroptosis associated with impaired tissue repair. Mechanistically, CCL5 was linked to the activation of the pyroptotic pathway through interactions with inflammasome components, promoting caspase-11-dependent gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) release. Network pharmacology analysis identified artesunate, a clinically approved antimalarial drug, as a potential inhibitor of CCL5 expression in patients with NARDS. Functional validation showed that artesunate attenuated M2 macrophage pyroptosis, reduced pulmonary injury, and promoted tissue repair. Collectively, our findings identify CCL5 as a potential regulator of macrophage pyroptosis and support the therapeutic potential of artesunate for modulating pyroptosis-associated inflammation in NARDS. This study provides a mechanistic framework for the development of CCL5-targeted interventions and highlights the dual anti-inflammatory and pro-repair properties of artesunate in NARDS treatment.