FoxO1a-mediated Edil3 transcription is impaired in macrophages and exacerbates lung injury after liver transplantation in the aged microenvironment

Acute lung injury (ALI) is a major complication after liver transplantation and is closely linked to hepatic ischemia-reperfusion injury-driven systemic inflammation through the liver-lung axis. Aging is associated with increased inflammatory susceptibility and impaired stress adaptation, which may aggravate post-transplant lung injury in the aged microenvironment. To investigate this, young and aged recipient mice underwent orthotopic liver transplantation under identical donor liver conditions. Mechanistic studies were performed using BALF macrophages and aged-like macrophage models in vitro. Lung injury was more severe in the aged microenvironment and was accompanied by enhanced oxidative stress, pulmonary edema, and inflammatory activation. Edil3 expression was significantly reduced in lung tissue, and notably, this reduction was observed in F4/80-positive macrophage-associated regions and in isolated BALF macrophages from aged recipients. Functional studies showed that Edil3 loss promoted macrophage inflammatory activation, whereas restoration of Edil3 alleviated inflammatory responses and improved epithelial barrier-related changes in vitro. FoxO1a was identified as an upstream transcriptional activator of Edil3. In the aged microenvironment, impaired Sirt1-FoxO1a interaction was associated with increased FoxO1a acetylation and reduced its protein stability, thereby suppressing Edil3 expression. Pharmacological activation of Sirt1 alleviated post-transplant lung injury. These findings indicate that disruption of the Sirt1/FoxO1a/Edil3 axis in BALF macrophages contributes to post-transplant ALI in the aged microenvironment and may represent a potential therapeutic target. As these findings are based on preclinical murine and in vitro macrophage models, further validation in clinical samples and patient cohorts is required to determine the translational relevance of this pathway.