Translational Medicine
Open Access

Abstract

Galanin Dictates Metabolic Reprogramming in Aberrantly Activated Fibroblasts to Reverse Established Cardiac Fibrosis

Lesia Savchenko, Rodica Anesia, Andrei Timotin, Alexander Kel, Dimitri Marsal, Ilenia Martinelli, Jerome Roncalli, Oksana Kunduzova*

Myocardial fibrosis is a common motif in Heart Failure (HF)-related fatalities. Persistent activation of fibroblasts triggers excessive fibrotic cascades culminating in cardiac fibrosis and dysfunction. However, molecular mechanisms orchestrating fibroblast activation are still obscure and as a result, effective strategies for limiting or reversing fibrosis are lacking. Here, we decrypted the metabolic phenotype of fibrosis-remodelled heart and unlocked bioactive peptide galanin as a metabolic checkpoint in aberrant fibroblast activation dictating fibrotic tissue remodeling. Integrated analysis of RNA-seq revealed a predominant role of galanin in metabolism of cardiac fibroblasts. Functional studies found that galanin calibrates metabolc reprogramming during fibroblast phenotypic switching from naïve to activated phenotype promoting myocardial fibrosis. In a mouse model of HF, chronic treatment with galanin promoted metabolic shift from fatty acid to glucose oxidation, mitochondrial biogenesis and blunted established myocardial fibrosis. Furthermore, we demonstrated that galanin reduced number of CD68-positive macrophages and preserved cardiac function in fibrosis-remodelled hearts. Mechanistically, galanin orchestrated metabolic behavior of aberrantly activated cardiac fibroblasts through the Forkhead box protein O1 (FoxO1) pathway. These findings unravel a previously unknown role of galanin in metabolic rewiring of cardiac fibroblast-tomyofibroblast transition dictating fibrosis resolution and provide a new metabolism-based angle for therapeutic intervention to tackle cardiac fibrosis.

Published Date: 2025-04-10; Received Date: 2024-04-07