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

BACKGROUND

Acute respiratory distress syndrome (ARDS) frequently develops after cardiopulmonary bypass (CPB), with lung ischemia/reperfusion injury (LIRI) as a major contributing factor. However, the role of fatty acid-binding protein 4 (FABP4) in the pathogenesis of CPB-associated ARDS remains poorly understood.

METHODS

Experimental LIRI models were established in vivo and in vitro to investigate the role of FABP4 in alveolar epithelial injury. Lipid droplets (LDs) accumulation, fatty acid (FA) metabolism, epithelial-mesenchymal transition (EMT), and alveolar epithelial barrier (AEB) integrity were assessed using molecular, cellular, and functional approaches. Pharmacological and genetic interventions were applied to evaluate the contribution of FABP4-mediated signaling pathways.

RESULTS

LIRI induced autocrine FABP4 signaling in alveolar epithelial cells, leading to pronounced LDs accumulation and disruption of AEB integrity. FABP4 activation enhanced FA metabolism and promoted EMT, which played a critical role in epithelial barrier dysfunction. Mechanistically, FABP4 activated the p38 MAPK pathway, resulting in ULK1 phosphorylation, suppression of lipophagy, and subsequent LDs formation, thereby driving EMT. Inhibition of LDs accumulation effectively attenuated EMT and alleviated AEB disruption.

CONCLUSION

FABP4 serves as a key metabolic regulator linking lipid reprogramming to EMT and alveolar epithelial barrier disruption during LIRI. Targeting FABP4-mediated lipid metabolism may represent a promising therapeutic strategy for preventing ARDS following CPB.

KEY POINTS: LIRI induces autocrine FABP4 signaling in alveolar epithelial cells. FABP4 promotes lipid droplets accumulation by inhibiting lipophagy through p38 MAPKULK1 signaling. FABP4-driven lipid metabolic reprogramming triggers EMT and disrupts alveolar epithelial barrier integrity. Targeting FABP4 or lipid droplets accumulation may offer therapeutic potential for CPB-associated ARDS.