Transformative Approaches to Biomarker Assessment and Clinical Profiles in Pulmonary Hypertension Patients : Short title: Biomarker Assessment and Clinical Profiles in Pulmonary Hypertension Patients.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder marked by elevated pulmonary arterial pressure, leading to right heart failure and high mortality. Emerging evidence links metabolic disturbances, renal dysfunction, and molecular dysregulation to PH pathogenesis. This study aimed to investigate biochemical and molecular biomarkers associated with PH, focusing on renal, metabolic, and vascular parameters. MATERIALS AND METHODS: A hospital-based case-control study was conducted at Al-Sadr Teaching Hospital, Iraq, from January to June 2024. Sixty-two PH patients and 30 age- and sex-matched healthy controls were recruited. Fasting venous blood samples were analyzed for urea, creatinine, glucose, insulin, uric acid, troponin I, homocysteine, and KCNK3. Insulin resistance (IR) was estimated using HOMA-IR. Comparisons between groups were performed using independent t-tests, correlations via Pearson's coefficient, and diagnostic performance assessed using ROC curve analysis. RESULTS: PH patients exhibited significantly elevated urea, creatinine, glucose, insulin, uric acid, homocysteine, and IR (P < 0.05) and reduced KCNK3 levels (P = 0.006) compared to controls. ROC analysis showed IR (AUC 0.903), homocysteine (AUC 0.762), and insulin (AUC 0.808) as effective discriminators of PH, whereas KCNK3 had limited diagnostic accuracy (AUC 0.350). Correlation analysis demonstrated positive associations between homocysteine and insulin/glucose, while KCNK3 inversely correlated with renal and metabolic parameters. Subgroup analysis indicated higher urea and glucose in male patients (P < 0.05). CONCLUSION: PH is associated with systemic metabolic dysregulation, renal impairment, and molecular alterations, including reduced KCNK3 and elevated homocysteine. Insulin resistance and homocysteine may serve as potential non-invasive biomarkers, highlighting the need for integrated biochemical and molecular assessment in PH management.