• Exercise-induced and pathological cardiac hypertrophy exhibit distinct proteomic profiles, with 46, 302, and 340 differentially expressed proteins identified in exercise vs control, isoproterenol vs control, and exercise vs isoproterenol comparisons, respectively.
• Acox1 and Gal-3 were identified as overlapping differentially expressed proteins across comparisons, suggesting their potential as intervention targets for pathological cardiac hypertrophy.
• Exercise may promote physiological cardiac hypertrophy by upregulating Acox1 to enhance fatty acid metabolism, whereas isoproterenol may induce pathological hypertrophy by downregulating Acox1, leading to peroxisome dysfunction and lipotoxicity.
• The study provides a comprehensive proteomic basis for understanding the molecular differences between physiological and pathological cardiac hypertrophy, offering novel therapeutic avenues for heart failure prevention.