Iron, arginine, and redox metabolism in peripheral blood mononuclear cells distinguishes sickle cell disease and pulmonary hypertension

Abstract Pulmonary hypertension (PH) is a severe vascular complication of sickle cell disease (SCD); yet, not all patients with SCD develop PH, and PH also arises independently. This duality underscores the need to understand their intersecting biology. We integrated metabolomic, proteomic, and elemental analyses of human peripheral blood mononuclear cells (PBMCs) from individuals with SCD, PH, combined SCD–PH, and healthy controls to define shared and distinct mechanisms. PBMCs from SCD patients, regardless of PH status, displayed significantly elevated intracellular iron, consistent with chronic hemolysis and erythrophagocytosis. Multi‐omic profiling revealed condition‐specific immune–metabolic signatures: SCD PBMCs showed mitochondrial suppression and reduced oxidative phosphorylation; PH PBMCs showed dysregulated arginine and creatine metabolism, implicating nitric oxide and polyamine pathways; and SCD–PH PBMCs displayed amplified hemoglobin/iron handling, oxidative stress, and immune activation. Unsupervised clustering confirmed discrete phenotypes, with greatest overlap between SCD and SCD–PH, reflecting the additive impact of hemolysis‐driven iron loading and PH‐driven metabolic remodeling. Histological validation of SCD–PH lung tissue demonstrated iron accumulation in perivascular macrophages, supporting a mechanistic link between systemic PBMC remodeling and pulmonary vascular pathology. Together, these findings establish PBMCs as a readily accessible compartment that mirrors disease‐specific metabolic and immune alterations. By capturing iron, arginine, and redox pathways across SCD, PH, and SCD–PH, our study positions PBMC profiling as a novel tool for mechanistic insight, patient stratification, and biomarker discovery and novel interventions.