Halofuginone Hydrobromide

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Halofuginone (HF) exerts beneficial effects on organ fibrosis, periodontitis, and cancer. However, the effect of HF against AF remains unknown. During the induction of AF, the rats were intragastrically administered HF (5 mg/kg and 10 mg/kg) daily for 7 consecutive days. Cardiac function was evaluated through echocardiographic analysis. The presence of pathological changes and interstitial fibrosis in the left atrial tissues were investigated. Intracellular Ca²⁺ homeostasis and mitochondrial function in atrial tissues were evaluated. The activation of the PI3K/Akt signaling pathway was examined, and an allosteric Akt inhibitor, MK-2206, was applied to confirm the involvement of the PI3K/Akt signaling pathway in the protection against AF by HF. The administration of HF resulted in a prolongation of the atrial effective refractory period (AERP), a reduction in both the duration and inducibility of AF, and a decrease in atrial weight, heart weight, atrial weight/body weight ratio, and heart weight/body weight ratio in rats with AF. In addition, the administration of HF resulted in a reduction in left atrial diameter (LAD) and an increase in left ventricular internal diameter diastolic (LVIDd), ejection fraction (EF), and fractional shortening (FS), while having no effect on left ventricular internal diameter systolic (LVIDs). The pathological changes and cardiac fibrosis observed in rats with AF were mitigated by HF. Moreover, HF enhanced mitochondrial function, suppressed cardiomyocyte apoptosis, and activated the PI3K/Akt pathway in AF rats. Furthermore, the protective effect against AF was also observed in an in vitro model. The effects of HF on fibrosis markers, intracellular Ca²⁺ homeostasis, mitochondrial function, and cardiac apoptosis were blocked by MK-2206. HF alleviated the susceptibility to AF in vivo and in vitro via the activation of the PI3K/Akt signaling pathway.

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.