Crucially, the mitochondrial fission and mitophagy inhibitor Mdivi-1 abolished all beneficial effects of NLRX1, underscoring the essential role of comprehensive mitochondrial quality control.<h4>Conclusion</h4>Our findings identify NLRX1 as a critical protective regulator of mitochondrial integrity that alleviates septic ALI by orchestrating mitophagy and mitochondrial quality control to restrain NLRP3-driven inflammation, presenting a promising therapeutic target. Here, NLRP3 is linked to acute respiratory distress syndrome.