Oleic acid promotes lung injury in hypertriglyceridaemia-associated acute pancreatitis via the PIEZO1/NR4A1/CPT1A axis impairing endothelial fatty acid oxidation.

BACKGROUND

Hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) is frequently complicated by acute lung injury (ALI), which worsens prognosis. Oleic acid (OA), a major circulating free fatty acid, may play a key role, but the underlying mechanism remains unclear.

OBJECTIVE

To investigate the relationship between plasma OA and HTG-AP-associated ALI and to explore the mechanism by which OA disrupts endothelial barrier through PIEZO1-mediated impairment of fatty acid oxidation (FAO).

DESIGN

This study used clinical sample analysis, an HTG-AP mouse model and OA-stimulated human umbilical vein endothelial cells. The association between OA and ALI was evaluated, and PIEZO1 was identified as a potential OA target through calcium imaging, transcriptomics and the Human Protein Atlas. Genetic/pharmacological interventions, lipidomics, Seahorse assays and barrier function tests were used to characterise FAO impairment and barrier disruption. NR4A1 regulation of CPT1A was investigated through transcriptomic and ChIP assays. Finally, the pathway's function was validated in mice with endothelial-specific Piezo1 knockdown.

RESULTS

Clinical and animal data showed elevated plasma OA in HTG-AP, positively associated with ALI incidence and severity. Multidimensional data identified PIEZO1 as a key target mediating OA-induced endothelial dysfunction. Mechanistically, OA activated and upregulated PIEZO1, which suppressed NR4A1 expression, leading to downregulation of CPT1A and impaired FAO, ultimately disrupting the endothelial barrier. Endothelial-specific Piezo1 knockdown significantly alleviated HTG-AP-associated ALI in mice.

CONCLUSION

OA promotes endothelial barrier dysfunction and exacerbates HTG-AP-associated ALI via the Piezo1/NR4A1/CPT1A axis by impairing FAO, offering a novel mechanistic insight and identifying potential therapeutic targets for HTG-AP-associated ALI.