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Pulmonary microvascular leakage is one of the characteristics of blood–air barrier dysfunction in septic acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Fibroblast growth factor-inducible 14 (Fn14) exerts diverse functions under certain circumstances. However, the role of Fn14 on the integrity of pulmonary microvascular endothelial cells (PMVECs) during sepsis remains unknown. Septic ALI was induced via cecal ligation and puncture (CLP). Fn14 expression on PMVECs was measured 24 h after surgery. The effects of Fn14 blockade on septic ALI were investigated in vivo and in vitro. Compared with the Sham group, Fn14 expressed in septic PMVECs was increased significantly 24 h after surgery. The protein level in bronchoalveolar lavage fluid, the lung wet to dry ratio, and neutrophil/macrophage infiltration in lungs were reduced in septic mice after Fn14 blockade. Similarly, ICAM-1 and MCP-1 levels were attenuated after Fn14 blockade or knockdown in lungs or human pulmonary microvascular endothelial cells (HPMECs). Furthermore, Fn14 silencing reduced Caspase-3 levels and upregulated the transendothelial electrical resistance level in TNF-like weak inducer of apoptosis-treated HPMECs. In addition, the degree of lung fibrosis was ameliorated and the survival of CLP mice was improved significantly after Fn14 blockade. In conclusion, Fn14 on PMVECs plays an important role in the progress of septic ALI. Fn14 blockade may prove to be an innovative lung-protective strategy for the treatment of septic ALI.