Abstract Background Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder caused by defects in lysosome-related organelles, leading to systemic manifestations that include pulmonary fibrosis in specific subtypes. Progressive lung fibrosis represents a major cause of morbidity and mortality in HPS. Identifying circulating protein biomarkers may enable earlier detection of fibrotic remodeling and inform targeted monitoring strategies. Primary Ciliary Dyskinesia (PCD), another inherited disorder characterized by chronic airway inflammation, rarely develops pulmonary fibrosis and thus provides an informative disease comparator. Objective To characterize circulating protein signatures distinguishing Hermansky-Pudlak Syndrome from Primary Ciliary Dyskinesia and healthy controls, and to determine whether these proteins are associated with pathways linked to pulmonary fibrosis. Methods Plasma samples were obtained from a total of 49 subjects; 10 with Hermansky-Pudlak Syndrome type 1 (mean age 39 years, range 22-50; 60% male), 14 with Primary Ciliary Dyskinesia (mean age 30 years, range 6-61; 43% male), and 25 age and sex matched healthy controls. Proteomic analysis was performed using the Nucleic Acid Linked Immunosorbent Assay (NULISA) platform to quantify circulating protein expression across groups. Results Proteomic analysis revealed significant upregulation of multiple inflammatory and immune-regulatory proteins in HPS compared to healthy controls, including TNFSF9, IL27, CD40LG, GDF15, MIF, CTF1, TAFA5, NGF, TNFSF8, CD276, ICOSLG, and CCL21, with downregulation of HLA-DRA and CSF1. Compared to PCD, HPS showed increased expression of macrophage- and T-cell-associated markers (TREM2, HAVCR1, BMP7, IL34, CD80, TNFSF8, CD4, CX3CL1, IL1R2, CSF2, CSF1R) and reduced levels of repair and vascular-stabilizing proteins (ANGPT1, CXCL14, SDC1, AGER). This pattern suggests activation of profibrotic and proinflammatory pathways specific to HPS rather than generalized airway inflammation representing potential biomarkers for disease progression. Conclusion Proteomic profiling using NULISA identified distinct proteins elevated in HPS compared with both healthy controls and PCD patients. These findings suggest early activation of fibrotic pathways and highlight candidate biomarkers for risk stratification and disease monitoring. Further studies are warranted to define their mechanistic roles and clinical utility in HPS-associated pulmonary fibrosis. This abstract is funded by: none
Varon et al. (Fri,) studied this question.