Beyond the Vasculature: The Emerging Role of Systemic Metabolism and Immunometabolism in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) has traditionally been viewed as a vasculocentric disorder, with current therapies failing to reverse vascular remodeling or address pervasive systemic metabolic abnormalities. This review synthesizes emerging evidence to propose a paradigm shift, conceptualizing PAH as a systemic metabolic-immunological network disease. It examines how metabolic dysfunction in peripheral organs (adipose tissue, liver, skeletal muscle) and immunometabolic reprogramming of immune cells (e.g., macrophages, lymphocytes) synergistically drive pathology. These components engage in dynamic crosstalk via circulating mediators (metabolites, adipokines, cytokines), creating a self-amplifying loop that fuel pulmonary vascular inflammation and remodeling. Key mechanisms explored include adipose tissue endocrine dysfunction (contributing to the obesity paradox), hepatic insulin resistance and bile acid signaling, skeletal muscle energy crisis and wasting, and the pivotal roles of macrophage glycolytic polarization and T-cell subset imbalance. Insulin resistance/hyperglycemia emerges as a central hub linking metabolic and immune dysregulation. The review concludes that future therapeutic strategies must move beyond vasodilation to target this systemic network, discussing the potential of repurposed metabolic agents, direct immunometabolic modulators, and integrated lifestyle interventions to disrupt disease progression.