Combined impact of ROR2 and its ligands on the pathogenesis and prognosis of idiopathic pulmonary fibrosis

Seung-Lee Park; Jong-Uk Lee; Min Kyung  Kim; Eunjeong  Seo; Myung-Shin Kim; Hun Gyu  Hwang; Jung Hyun  Kim; Hun Soo  Chang; Choon-Sik Park

doi:10.36141/svdld.2026.17921

Combined impact of ROR2 and its ligands on the pathogenesis and prognosis of idiopathic pulmonary fibrosis

Authors

Seung-Lee Park Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang University, Asan, Republic of Korea
Jong-Uk Lee Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
Min Kyung Kim Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang University, Asan, Republic of Korea
Eunjeong Seo Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang University, Asan, Republic of Korea
Myung-Shin Kim Division of Allergy and Respiratory Disease, Soonchunhyang University Gumi Hospital, Gumi, Republic of Korea
Hun Gyu Hwang Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
Jung Hyun Kim Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
Hun Soo Chang Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
Choon-Sik Park Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea

Keywords:

ROR2, idiopathic Pulmonary Fibrosis (IPF), Wnt proteins, Bronchoalveolar lavage fluid, Mortality

Abstract

Background and aim: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by aberrant fibroblast activation and extracellular matrix accumulation. Although ROR2 signaling via Wnt ligands has been implicated in fibrosis, their integrated clinical relevance in IPF remains unclear. This study investigated the clinical significance of ROR2 and its ligands—WNT1, WNT5A, and WNT7A—in IPF development and prognosis.

Methods: Bronchoalveolar lavage (BAL) fluid was collected from 124 IPF patients and 17 controls. Protein levels of ROR2, WNT1, WNT5A, and WNT7A were measured using ELISA. Immunofluorescence staining was performed to evaluate cellular localization. Cox proportional hazards analysis with backward elimination was used to identify mortality risk factors. Kaplan–Meier and log-rank tests were used to compare cumulative mortality between subgroups.

Results: The levels of ROR2 and WNT7A were significantly higher in IPF compared to controls (p < 0.001 and p = 0.030, respectively). Among the proteins analyzed (ROR2, WNT1, WNT5A, and WNT7A), only elevated ROR2 levels were independently associated with increased mortality (hazard ratio [HR] = 2.32, p = 0.026), whereas WNT1, WNT5A, and WNT7A did not show significant associations with survival after correction for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method. Immunofluorescence analysis demonstrated co-localization of ROR2 with COL1A1-positive fibroblasts, as well as with WNT1, WNT5A, and WNT7A. Exploratory stratification based on combined ROR2 and WNT5A expression identified a subgroup with low ROR2 / high WNT5A levels that showed a trend toward better prognosis.

Conclusion: ROR2 levels in BAL fluid are independently associated with IPF pathogenesis and prognosis, and may serve as a useful biomarker for identifying molecular endotypes and assessing clinical risk. Exploratory findings suggest that ROR2 and its ligand may modulate prognosis in a subset of patients.

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