Inhibition of PARP1-mediated parthanatos by rucaparib phosphate alleviates sepsis-induced acute lung injury.

Sepsis is a life-threatening syndrome of organ dysfunction caused by a dysregulated host response to infection and is frequently complicated by acute lung injury (ALI). PARP1-dependent parthanatos has been implicated in sepsis pathogenesis, but whether pharmacological PARP1 inhibition by rucaparib phosphate (RP) protects against sepsis-associated ALI remains unclear. Here, we investigated the effects of RP in LPS-stimulated RAW 264.7 macrophages, MLE-12 alveolar epithelial cells, and an LPS-induced mouse model of septic lung injury. Lung injury and barrier disruption were assessed by hematoxylin and eosin staining, lung wet-to-dry ratio, bronchoalveolar lavage fluid (BALF) protein content, immunoblotting, immunofluorescence, and histological scoring. Parthanatos and cellular stress were evaluated by PARP1/PAR expression, AIF subcellular localization, TUNEL staining, ROS measurement, γ-H2AX expression, 8-OHdG levels, and comet assays, whereas inflammatory responses were quantified by ELISA. RP suppressed LPS-induced PARP1 activation, PAR accumulation, AIF nuclear translocation, DNA damage, and ROS generation. RP also preserved ZO-1 and E-cadherin expression and membrane localization, indicating protection of alveolar epithelial barrier integrity. In vivo, RP reduced lung edema, BALF protein leakage, inflammatory cytokine production, histological injury, and pulmonary cell death in LPS-challenged mice. Collectively, these findings indicate that RP attenuates LPS-induced acute lung injury and suppresses key molecular features associated with PARP1-dependent parthanatos (PARP1 hyperactivation, PAR accumulation, and AIF nuclear translocation) while preserving alveolar epithelial barrier integrity. Pharmacological PARP inhibition therefore represents a promising preclinical therapeutic candidate that warrants further validation in clinically relevant models of sepsis-associated ALI.