Cardiometabolic Multimorbidity and Sympathetic Overactivity: Translational Rationale for Combined Hepatic-Renal Denervation.

Cardiometabolic multimorbidity, encompassing type 2 diabetes, hypertension, and metabolic dysfunction-associated steatotic liver disease, is closely linked to sympathetic nervous system overactivity and remains suboptimally controlled by pharmacotherapy alone. This state-of-the-art review evaluates the biological rationale, technical feasibility, preclinical evidence, and emerging clinical data supporting combined hepatic and renal denervation as an investigational neuromodulatory strategy for cardiometabolic disease. Preclinical models suggest that multiorgan denervation may modulate sympathetic activity and metabolic pathways, whereas early first-in-human studies of celiac-hepatic denervation indicate feasibility and acceptable short-term safety. However, current human evidence remains limited by small sample sizes, single-arm designs, and the absence of sham-controlled trials, precluding definitive conclusions regarding efficacy, durability, and causal mechanisms. Combined hepatic-renal denervation should therefore be regarded as a translational-stage, hypothesis-generating approach. Rigorous randomized trials are required to define target engagement, safety, durability, and clinical relevance.