Elevated GFI1 in Alveolar Macrophages Suppresses ACOD1 Expression and Exacerbates Lipopolysaccharide-Induced Lung Injury in Obesity.
Summary
This mechanistic study links obesity to aggravated ALI via suppression of ACOD1 in alveolar macrophages, driven by elevated GFI1 and modulated through Nrf2 signaling. ACOD1 overexpression was protective, while its knockdown worsened injury, highlighting the itaconate/Nrf2 pathway as a candidate therapeutic axis.
Key Findings
- ACOD1 expression is significantly decreased in lung tissue and alveolar macrophages from obese (HFD) mice and clinical samples.
- ACOD1 knockdown exacerbates lung injury, inflammation, and oxidative stress; overexpression mitigates these effects.
- Nrf2 inhibition attenuates the protective effects of ACOD1 overexpression in obesity-aggravated ALI.
- GFI1 protein is elevated in alveolar macrophages in obesity; GFI1 knockdown upregulates ACOD1.
Clinical Implications
While preclinical, findings support exploring ACOD1/itaconate augmentation or GFI1 inhibition and Nrf2 activation as macrophage-targeted strategies in obese patients at risk of ALI/ARDS.
Why It Matters
It uncovers a previously unappreciated GFI1–ACOD1–Nrf2 immunometabolic pathway driving obesity-aggravated lung injury, offering testable targets for ARDS/ALI.
Limitations
- Preclinical study with limited direct clinical endpoints.
- Sample sizes and comprehensive data-sharing details are not specified in the abstract.
Future Directions
Evaluate pharmacologic activation of ACOD1/itaconate and Nrf2, or GFI1 inhibition, in obese ALI/ARDS models and pilot translational studies; define macrophage-targeted delivery strategies.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from animal and cellular experiments with human sample correlation.
- Study Design
- OTHER