A narrative review of the mitochondrial DNA-stimulated inflammatory axis in sepsis-induced acute lung injury: cellular mechanisms and therapeutic targeting.

Sepsis-induced acute lung injury (SALI) represents a life-threatening condition with complex pathophysiology. Emerging evidence highlights the mitochondrial DNA (mtDNA)-stimulated inflammatory axis as a pivotal mechanism driving pulmonary inflammation. This narrative review elucidates how mtDNA, released upon cellular damage, acts as a potent damage-associated molecular pattern that activates the cyclic guanosine monophosphate-adenosine monophosphate(cGAMP) synthase-stimulator of interferon genes (STING) pathway. We detail the cell type-specific roles of this axis: In macrophages, it promotes M1 polarization and pyroptosis; in neutrophils, it facilitates neutrophil extracellular trap formation; in lymphocytes, it contributes to T-cell exhaustion; and in structural cells (endothelial and alveolar epithelial cells, fibroblasts), it induces barrier dysfunction, PANoptosis, and fibrotic remodeling. Furthermore, we discuss promising therapeutic strategies that target this axis, including STING inhibitors, mtDNA-neutralizing nanoparticles, and natural compounds, which have shown efficacy in preclinical models. Translating these findings into clinical practice requires future research focused on cell-specific modulation and innovative delivery systems to mitigate the devastating effects of SALI.