The potential lipid biomarker 5-HETE for acute exacerbation identified by metabolomics in patients with idiopathic pulmonary fibrosis.

Background and objective: Acute exacerbation (AE) is often the fatal complication of idiopathic pulmonary fibrosis (IPF). Emerging evidence indicates that metabolic reprogramming and dysregulation of lipid metabolism are distinctive characteristics of IPF. However, the lipid metabolic mechanisms that underlie the pathophysiology of AE-IPF remain elusive.

Methods: Serum samples for pilot study were collected from 34 Controls, 37 stable IPF (S-IPF) cases and 41 AE-IPF patients. UHPLC-MS/MS was utilized to investigate metabolic variations and identify lipid biomarkers in serum. ELISA, quantitative PCR and western blot were employed to validate the identified biomarkers.

Results: There were 32 lipid metabolites and 5 lipid metabolism pathways enriched in all IPF patients compared to Controls. In AE-IPF versus S-IPF, 19 lipid metabolites and 12 pathways were identified, with 5-hydroxyeicosatetraenoic Acid (5-HETE) significantly elevated in AE-IPF. Both in internal and external validation cohorts, the serum levels of 5-HETE were significantly elevated in AE-IPF patients compared to S-IPF subjects. Consequently, the indicators related to 5-HETE in lipid metabolic pathway were significantly changed in AE-IPF patients compared with S-IPF cases in the lung tissues. The serum level of 5-HETE was significantly correlated with the disease severity (CT score and PaO₂/FiO₂ ratio) and survival time. Importantly, the receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Multivariate Cox regression analysis demonstrated that 5-HETE represents a promising lipid biomarker for the diagnosis and prognosis of AE-IPF.

Conclusion: Our study highlights lipid reprogramming as a novel therapeutic approach for IPF, and 5-HETE may be a potential biomarker of AE-IPF patients.