Chronic β-Blockade and Systemic Homeostasis: Molecular Integration of Cardiorenal and Immune Pathways, a Narrative Review

β-blockers (BBs) remain a cornerstone therapy for cardiovascular disorders, reducing heart rate, blood pressure, and arrhythmia risk. Yet, their influence extends well beyond the heart, impacting renal function, inflammatory responses, metabolism, and endocrine balance. Although cardio-selective BBs are designed to minimize off-target effects, they still modulate immune signaling and hormonal pathways, producing paradoxical outcomes. Suppression of sympathetic tone and RAAS activity underpins therapeutic benefit but may also contribute to renal hypoperfusion, electrolyte imbalance, and pro-inflammatory changes, especially in patients receiving combination therapy with RAAS inhibitors or diuretics. Genetic polymorphisms (e.g., ADRB1, GRK5, eNOS, CYP2D6) and comorbidities further shape individual responses. This review integrates cardiovascular, renal, and immune perspectives to map the pathways by which BBs influence systemic homeostasis, highlighting cytokine interactions and disease-specific remodeling. We emphasize the need for personalized, biomarker-guided strategies, leveraging pharmacogenomics, multi-omics, and machine learning tools to optimize BB selection and dosing. By reframing BBs as dynamic modulators of the cardio-renal-immune axis, this review advances their role in precision cardiovascular medicine.