Therapeutic Regression of Myocardial Fibrosis by Retatrutide via p-AMPK/TGF-β1 Signaling Pathways

Introduction and Relevance: Heart failure with preserved ejection fraction (HFpEF) represents one of the most complex and burgeoning clinical challenges in modern medicine. Progressive myocardial interstitial fibrosis, extracellular matrix disorganization, and ventricular wall stiffening constitute the primary pathophysiological foundation of the disease. Since HFpEF is tightly linked to systemic cardiometabolic disorders (visceral obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis — MASH), traditional neurohumoral cardiotropic therapy remains entirely ineffective against it. The purpose of this review is to evaluate the precise molecular mechanisms of action of a novel triple incretin receptor agonist (a multi-agonist of GLP-1/GIP/GCGR receptors — Retatrutide), specifically through the prism of activating the intracellular protective enzyme — p-AMPK and suppressing the profibrotic TGF-β1 cascade.

Methods: A systematic analysis, comparative evaluation, and data synthesis of 10 high-impact international preclinical, molecular, and pharmacological studies published recently in PubMed, Nature, Circulation, and The Lancet databases was conducted.

Results and Conclusion: Comprehensive analysis of literature data confirms that triple receptor agonism robustly potentiates intracellular cAMP/PKA signaling, ensuring effective phosphorylation of the cellular metabolic sensor — AMPK at the threonine-172 residue (p-AMPK). Activated p-AMPK directly suppresses components of the profibrotic TGF-β1/Smad3 signaling pathway, blocking the nuclear translocation of messenger proteins and fully halting excessive collagen synthesis. This paper biologically substantiates the unique potential of triple agonists not only for the prevention of fibrosis but also for the therapeutic reversal (regression) of already established structural scar configurations.