FABP4-mediated lipid droplet accumulation drives epithelial-mesenchymal transition and aggravates alveolar epithelial barrier disruption.

Summary

In LIRI models, alveolar epithelial cells upregulated FABP4 autocrine signaling, which inhibited lipophagy via p38 MAPK–ULK1, leading to lipid droplet accumulation, enhanced FA metabolism, EMT, and alveolar epithelial barrier disruption. Pharmacologic/genetic inhibition of FABP4 or lipid droplet formation mitigated EMT and barrier dysfunction, highlighting FABP4 as a potential therapeutic target for CPB-associated ARDS.

Key Findings

• LIRI induces autocrine upregulation of FABP4 in alveolar epithelial cells, driving lipid droplet (LD) accumulation.
• FABP4 activates p38 MAPK leading to ULK1 phosphorylation, suppression of lipophagy (lipid-selective autophagy) and consequent LD formation.
• FABP4-driven lipid metabolic reprogramming promotes EMT and disrupts alveolar epithelial barrier integrity; inhibiting LD accumulation attenuates EMT and barrier disruption.

Clinical Implications

Translational potential: FABP4 or pathways controlling lipophagy could be targeted to prevent ARDS after cardiopulmonary bypass or other ischemia–reperfusion lung injuries, but clinical trials are required since current evidence is preclinical.

Limitations

• Preclinical models only—no human tissue validation reported in abstract.
• Therapeutic efficacy and safety of FABP4 targeting in clinically relevant settings remain untested.

Future Directions

Validate FABP4 and lipophagy markers in human CPB and ARDS samples, test FABP4 inhibitors or lipophagy modulators in larger animal models, and design early-phase clinical trials if safety is acceptable.