Natriuretic Peptide Receptor-C (NPR3) in Pulmonary Hypertension Associated with Chronic Lung Disease: A PRISMA-ScR Scoping Review of Diagnostic, Prognostic, Mechanistic, and Therapeutic Evidence

Background/Objectives: Pulmonary hypertension associated with chronic lung disease remains difficult to diagnose, phenotype, and manage because vascular remodeling, parenchymal lung injury, hypoxemia, inflammation, fibrosis, and right ventricular dysfunction often coexist. Natriuretic peptides are widely used as cardiopulmonary biomarkers, but the receptor-level role of natriuretic peptide receptor-C, encoded by NPR3, remains incompletely defined. This scoping review mapped original empirical evidence on NPR-C/NPR3 and related C-type natriuretic peptide biology in pulmonary hypertension, chronic lung disease, pulmonary vascular remodeling, and right ventricular adaptation. Methods: This scoping review was conducted and reported in accordance with PRISMA-ScR, with applicable PRISMA 2020 reporting elements addressed where relevant to a scoping review. Searches of PubMed/MEDLINE and APA PsycINFO identified 72 records. After removal of 2 duplicates, 70 records underwent title and abstract screening. Forty-two records were excluded at this stage, and 28 reports were sought for full-text retrieval. All reports were retrieved and assessed for eligibility. Eleven reports were excluded at full-text review, leaving 17 original studies for inclusion in the evidence map. Reviews, meta-analyses, editorials, commentaries, protocols, and non-original reports were excluded from the synthesis. Results: The included studies comprised clinical biomarker studies, transcriptomic and receptor-expression analyses, experimental pulmonary hypertension models, chronic lung injury or fibrosis models, and pulmonary vascular cellular studies. Human evidence directly addressing chronic lung disease-associated pulmonary hypertension was limited and largely biomarker-centered, with CNP or NT-proCNP signals suggesting potential relevance to pulmonary vascular stress but without definitive NPR-C/NPR3 validation. Experimental studies supported biologic plausibility, linking CNP/NPR-C-related pathways to endothelial function, pulmonary vascular remodeling, smooth muscle and fibroblast behavior, hypoxic signaling, fibrosis, and right ventricular remodeling. However, findings varied across models, and receptor-specific attribution to NPR-C/NPR3 was often incomplete. Conclusions: Current evidence suggests that NPR-C/NPR3 is a biologically plausible but not yet clinically validated pathway in pulmonary hypertension associated with chronic lung disease. The strongest gap is the absence of prospective human studies integrating invasive hemodynamics, lung disease phenotyping, CNP/NT-proCNP profiling, NPR3 expression or genetic assessment, receptor-level biology, and right ventricular outcomes. Future studies should determine whether NPR-C/NPR3 can improve phenotyping, risk stratification, or therapeutic targeting in chronic lung disease-associated pulmonary hypertension.