FGF2 Attenuated Inflammation-Mediated Cardiac Damage: A Novel Mechanistic Insight into the AMPK-FUNDC1-Mitophagy

Septic cardiomyopathy, a severe complication of sepsis, is characterized by high morbidity and mortality rates, and its effective management remains an important challenge. Although fibroblast growth factor 2 (FGF2) has been shown to exert cardioprotective effects, its role in septic cardiomyopathy has not been extensively investigated. To address this knowledge gap, FGF2 knockout (FGF2^-/-) mice were injected with lipopolysaccharide (LPS) to establish septic cardiomyopathy in vivo, and the resulting cardiac injury was evaluated after 72 h. The results demonstrated that LPS inhibited FGF2 expression in cardiomyocytes, and genetic ablation of FGF2 exacerbated myocardial inflammation, oxidative stress, apoptosis, and cardiac dysfunction. Notably, treatment with recombinant FGF2 (rFGF2) effectively reversed these detrimental effects. Proteomic analysis revealed that FGF2 significantly modulated mitophagy, and further verification assays confirmed that FGF2 prevented LPS-induced mitochondrial injury and followed apoptosis by activating FUNDC1-mediated mitophagy. Molecular studies demonstrated that rFGF2 triggered the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, leading to the activation of FUNDC1-mediated mitophagy, which in turn mitigated myocardial mitochondrial injury and apoptosis. These findings suggest that FGF2 exerts its cardioprotective effects in septic cardiomyopathy by activating the AMPK-FUNDC1-mediated mitophagy pathway, thereby providing a potential therapeutic strategy for mitigating sepsis-induced cardiac damage.