The Cardio-Renal-Hepatic Axis in MASLD. Role of BDNF, NGF, and Metabolic Cross-Talk

Abstract

PURPOSE OF REVIEW: To evaluate the crosstalk between the liver, heart, and kidneys in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), highlighting the distinct regulatory roles of non-traditional hepatokines, and to assess shared therapeutic targets and molecular mechanisms driving cardiorenal complications in MASLD patients. RECENT FINDINGS: Emerging evidence highlights that hepatic lipid accumulation drives cardiac damage, which manifests as adverse remodeling, diastolic dysfunction, and coronary microvascular dysfunction. These abnormalities are mediated primarily by systemic lipotoxicity, inflammation of epicardial adipose tissue, and a pro-thrombotic environment. Mechanistically, altered hepatokine signaling mediates systemic cross-talk. Specifically, the downregulation of cardioprotective and renoprotective brain-derived neurotrophic factor (BDNF) and the dual metabolic roles of nerve growth factor (NGF), fibroblast growth factor (FGF) 19, and FGF21 accelerate the progression of both heart failure and chronic kidney disease (CKD). Concurrently, metabolic therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and peroxisome proliferator-activated receptor (PPAR) agonists demonstrate significant efficacy in ameliorating steatosis, inflammation, and overall metabolic outcomes. MASLD acts as a systemic driver of multi-organ dysfunction within the cardio-renal-hepatic axis. Profiling specific hepatokine signatures offers a promising frontier for identifying novel therapeutic targets and biomarkers of disease acceleration. Furthermore, while current metabolic therapies show remarkable potential, rigorous clinical testing remains critical to definitively determine whether their cardiovascular and renal benefits stem from direct tissue-specific protective mechanisms or secondary metabolic improvements.