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Low molecular weight heparin alleviates acute lung injury by suppressing ferroptosis involving the ROS/NRF2/HO-1
Yiting He1, Liangming Wu2, Songtao Liu2
1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Respiratory and Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
Background:
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening disorders. Low molecular weight heparin (LMWH), commonly used for the treatment of thrombotic complication, has been reported to be beneficial for ALI/ARDS. However, how LMWH modulates the development of lung injury remains unclear. In this study, we investigated the effects of LMWH on ALI and its mechanisms on ferroptosis.
Method:
LPS-induced ALI mouse model was established to evaluate the protective effects of LMWH in vivo. Human pulmonary endothelial cell (HPMECs) treated with LPS were used to explore the effects of LMWH on ferroptosis in vitro, with a positive control of NAC. Indicators such as Fe2+ level, mitochondrial dynamics related proteins were evaluated to determine the ferroptosis and mitochondrial function. RNA sequencing was utilized to uncover the potential molecular mechanisms.
Result:
In vivo, LMWH treatment significantly alleviated LPS-induced lung injury in mice, accompanied by a reduction in ferroptosis-related indicators. Consistently, in vitro studies using LPS-stimulated HPMECs revealed that LMWH suppressed ferroptosis, reduced ROS production, and ameliorated mitochondrial dysfunction. Pretreatment of ferroptosis inhibitor, ferrostatin (fer-1) mirrors the protective effects of LMWH against LPS-induced ferroptosis. Transcriptomic sequencing further demonstrated that LMWH downregulated LPS-induced transcription of HMOX1, decreased the release of cytochrome c resulting from mitochondrial dysfunction, and inhibited HO-1-mediated degradation of cytochrome c-a process known to liberate iron and exacerbate ferroptosis. The co-administration of hemin, an HMOX1 (HO-1) agonist, partially reversed the protective effects of LMWH. Mechanistically, LMWH attenuated ROS generation and subsequently suppressed ROS-mediated activation of the NRF2-HO-1 pathway. Collectively, these findings suggest that LMWH mitigates LPS-induced ferroptosis and lung injury primarily by inhibiting ROS overproduction and the downstream NRF2-HO-1 signaling cascade.
Conclusion:
Application of LMWH in ALI/ARDS may improve mitochondrial function and reduce HO-1 expression by suppressing ROS production, thereby mitigating ferroptosis. Together, these findings suggested that LMWH could be a therapeutic option for ALI/ARDS.
