Acute respiratory distress syndrome FXR/Sptlc2 signaling promotes alveolar macrophage mitophagy and limits lung inflammation

Alveolar macrophages (AMs) undergo functional reprogramming that critically regulates lung inflammation. Although mitophagy is essential for mitochondrial quality control, its role in macrophage functional reprogramming during acute respiratory distress syndrome (ARDS) remains unclear. Here, we identify the nuclear receptor Nr1h4 (FXR) as a transcriptional regulator of mitophagy in AMs. FXR activation transcriptionally upregulates serine palmitoyltransferase long chain base subunit 2 (Sptlc2), thereby enhancing mitophagy and promoting an anti-inflammatory macrophage phenotype under inflammatory conditions. The FXR/Sptlc2 axis reduces oxidative stress and inflammatory mediator production while increasing anti-inflammatory markers. Conversely, FXR deficiency impairs mitophagy, exacerbates pulmonary inflammation, and aggravates lung injury in vivo. These findings establish the FXR/Sptlc2 axis as a regulator of mitochondrial quality control and macrophage functional reprogramming and identify it as a potential therapeutic target in ARDS.