FGF21 alleviates diabetic vasculopathy with NF-κB suppression and fibrinolytic activation

Fibroblast growth factor 21 (FGF21) holds promise as a therapeutic agent for type 2 diabetes mellitus (T2DM), yet its specific role and mechanisms in mitigating diabetic vascular complications - the primary drivers of diabetes-related morbidity and mortality - remain incompletely defined, limiting its therapeutic potential. Here, we investigated FGF21-mediated mitigation of hyperglycemia-induced endothelial dysfunction and thrombosis using db/db diabetic mice and high glucose-stimulated EA.hy926 cells. Daily intraperitoneal administration of recombinant FGF21 (0.5 or 2 mg/kg) for 28 days lowered blood glucose levels significantly, improved insulin sensitivity, and alleviated histopathological damage in the carotid arteries, livers, kidneys, and spleens of diabetic mice. FGF21 also dose-dependently reduced endothelial apoptosis and oxidative stress by suppressing high glucose-induced reactive oxygen species (ROS) overproduction. Crucially, FGF21 restored fibrinolytic balance by elevating the serum levels of tissue-type and urokinase-type plasminogen activators (tPA/uPA), while reducing those of hypercoagulability markers, such as sP-selectin. Transcriptomic and molecular analyses revealed that FGF21 inhibited Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation, shown by reduced IκBα phosphorylation and p65 nuclear translocation, thereby downregulating pro-inflammatory mediators. Knockdown of β-klotho with siRNA negated the protective effects of FGF21, confirming its β-klotho-dependent efficacy. The findings reveal a dual mechanism by which FGF21 alleviates diabetic vascular complications: (1) through NF-κB-driven anti-inflammatory and antioxidant effects, and (2) by reactivation of the fibrinolytic system. The results provide new insights into the development of FGF21 as a novel, non-insulin, long-term hypoglycemic agent with the potential to address the critical unmet need of preventing or treating life-threatening diabetic vascular complications.