PCSK6 and clinical outcomes in the Pulmonary Fibrosis Foundation Patient Registry.

BACKGROUNDHigher plasma proprotein convertase subtilisin/kexin type 6 (PCSK6) concentration has been associated with increased all-cause mortality in idiopathic pulmonary fibrosis (IPF). Its role across the broader spectrum of fibrotic interstitial lung disease (ILDs) remains unclear. We examined associations between PCSK6 and respiratory outcomes in participants with pulmonary fibrosis in the Pulmonary Fibrosis Foundation Patient Registry and evaluated its expression in fibrotic lungs.

METHODSPCSK6 concentration was measured in plasma from 428 participants with fibrotic ILD using ELISA and tested for association with time to death, lung transplant, first respiratory hospitalization, and 10% decline in forced vital capacity (FVC) using adjusted Cox models. Single-cell RNA sequencing (scRNA-seq) data obtained from the IPF Cell Atlas were used to examine PCSK6 expression across disease states.

RESULTSPCSK6 levels were not significantly associated with time to death, lung transplantation, respiratory hospitalization, or 10% FVC decline in the overall cohort, or in the subgroup of participants with usual interstitial pneumonia pattern of fibrosis. Among participants with IPF, higher PCSK6 was associated with reduced survival, consistent with prior findings. scRNA-seq of fibrotic lungs demonstrated high PCSK6 expression in HAS1 + fibroblasts.

CONCLUSIONPCSK6 was not associated with worse respiratory outcomes in mixed fibrotic ILD but was associated with reduced survival in IPF. Its enrichment in HAS1 + fibroblasts suggests this pathway may be specific to IPF pathogenesis.

SUPPLEMENTARY INFORMATIONThe online version contains supplementary material available at 10.1186/s12931-026-03642-1.