Transcription Factor GATA3 Ameliorates Sepsis–Associated Acute Respiratory Distress Syndrome by Activating Smad1/5–YAP Pathway via BMP9

BMP9 protects against sepsis-induced lung injury. This research aimed to explore how BMP9 affects sepsis-associated acute respiratory distress syndrome (ARDS). Mice and MLE12 cells overexpressing BMP9 were treated with LPS to induce ARDS. Changes in ARDS-related pathological features, ferroptosis, BMP9 expression, and the Smad1/5-YAP pathway were analyzed. Regulation of BMP9 in the Smad1/5 pathway was investigated using the Smad pathway inhibitor LDN193189 and loss-of-function assays. The potential transcription factor of BMP9 was identified using the GEO and ChEA databases and validated through ChIP-qPCR, luciferase reporter assay, and functional experiments. LPS-induced mice exhibited severe lung injury, accompanied by increased inflammation, oxidative stress, and ferroptosis. Furthermore, LPS induction notably decreased BMP9, p-Smad1/5, and YAP levels in mice. BMP9 overexpression alleviated ARDS symptoms and ferroptosis while activating the Smad1/5-YAP pathway. LPS induction reduced cell viability and promoted inflammation, oxidative stress, and ferroptosis in MLE-12 cells, but BMP9 overexpression reversed these changes. Importantly, the protective effects of BMP9 overexpression were weakened by LDN193189 or by Smad1/5 or YAP knockdown. GATA3 was identified as the upstream transcription factor of BMP9, binding upstream of the BMP9 promoter region and activating its transcription. GATA3 knockdown significantly downregulated BMP9 expression in MLE-12 cells. GATA3 expression was notably decreased in ARDS models. In MLE-12 cells overexpressing BMP9, GATA3 knockdown markedly downregulated BMP9, p-Smad1/5, and YAP levels, thereby aggravating ARDS, whereas overexpression of GATA3 exerted protective effects in LPS-treated MLE-12 cells with BMP9 knockdown. In conclusion, GATA3 activates BMP9 transcription, thereby reducing inflammation and ferroptosis in sepsis-associated ARDS via the Smad1/5-YAP pathway.