Galectin-3 C-epitope, ANP, PPIA, and albumin function as drug-responsive panel biomarkers and therapeutic targets in aging and pressure overload-induced cardiac hypertrophy

ABSTRACT Biological aging (BA) and pressure overload-induced cardiac hypertrophy (PO-CH) are marked by myocardial thickening, fibrosis, and functional decline, culminating in an increased risk of heart failure. Effective clinical management requires biomarkers that not only track disease progression but also monitor therapeutic response. Using Amalaki Rasayana (AR), a cardioprotective nutraceutical-based medicine, in rat models of BA and PO-CH, we identified a panel of serum biomarkers whose treatment-induced decline was associated with disease regression. Among them, galectin-3 emerged in both full-length and oligomeric C-epitope cleaved forms, with the latter closely linked to pathological surface remodeling. Treatment with AR and its bioactive component gallic acid (GA) suppressed extracellular galectin-3 C-epitope oligomer accumulation by inhibiting full-length galectin-3 secretion through phosphorylation-dependent mechanisms and promotion of intracellular retention. Concurrently, serum levels of atrial natriuretic peptide (ANP), cyclophilin A (PPIA), and albumin (ALB) were consistently modulated by therapy. Validation in sera from elderly individuals and cardiac hypertrophy patients responding to conventional treatments supported the translational relevance of this biomarker panel. These findings establish a novel, mechanistically grounded biomarker set—galectin-3 C-epitope, ANP, PPIA, and ALB—for monitoring therapeutic response in cardiac hypertrophy, and position AR as a promising medicinal intervention against age- and pressure-induced cardiac pathology. GRAPHICAL ABSTRACT HIGHLIGHTS Galectin-3 C-epitope, ANP, PPIA, and ALB are elevated in aging and pressure overload driven left ventricular hypertrophy. Amalaki rasayana (AR) and Gallic Acid (GA) reduce these markers in cardiac tissue and circulation. AR and GA inhibit galectin-3 secretion and oligomeric binding to cardiomyocyte surfaces. AR and GA regulation predominantly occurs via phosphorylation-dependent cytoplasmic retention of galectin-3. These markers serve as potential therapeutic targets and diagnostic biomarkers.