Elevated GFI1 in Alveolar Macrophages Suppresses ACOD1 Expression and Exacerbates Lipopolysaccharide‐Induced Lung Injury in Obesity

Abstract To investigate the mechanisms behind the worsening of acute lung injury (ALI) in obesity, transcriptomic sequencing is performed, and significantly reduced mRNA levels of Aconitate Decarboxylase 1 (ACOD1) in the lung tissue of high‐fat diet (HFD) mice are found. Clinical samples are collected, an ALI model is established in HFD mice, and both human and mouse samples are analyzed, revealing a significant decrease in ACOD1 expression in lung tissue and alveolar macrophages in obesity. Further in vivo and in vitro experiments show that ACOD1 knockdown worsens lung injury, inflammation, and oxidative stress, while ACOD1 overexpression alleviates these effects. Moreover, nuclear factor erythroid 2‐related factor 2 (Nrf2) inhibition diminishes the protective effects of ACOD1 overexpression in ALI exacerbated by obesity. Additionally, in the context of obesity, growth factor independent 1 (GFI1) protein levels are elevated in alveolar macrophages, and its knockdown leads to upregulated ACOD1 expression. Therefore, this study suggests that ACOD1 downregulation in alveolar macrophages is a key factor in worsening ALI in obesity, likely driven by GFI1 upregulation.