The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.
Summary
In mouse and pig models, halofuginone produced weight loss by suppressing intake and enhancing energy expenditure, while improving insulin resistance and steatosis. Mechanistically, it activated the integrated stress response, elevating endocrine factors GDF15 and FGF21.
Key Findings
- Halofuginone reduced food intake, increased energy expenditure, and induced weight loss in diet-induced obese mice.
- Improved insulin resistance and hepatic steatosis accompanied weight loss.
- Mechanism: activation of integrated stress response with elevations of FGF21 and GDF15.
- Efficacy signals extended to a large-animal (pig) model, supporting translational potential.
Clinical Implications
If safety and efficacy translate to humans, halofuginone or ISR-tuned analogs could complement or serve as alternatives to incretin-based anti-obesity drugs, particularly in patients intolerant to GLP-1 RAs.
Why It Matters
Repurposes an approved drug to trigger endogenous anorectic and metabolic hormones (GDF15, FGF21), suggesting a translational path for obesity therapy beyond GLP-1–based approaches.
Limitations
- Preclinical; human safety, dose, and efficacy remain untested for obesity endpoints
- Potential ISR-related toxicities and off-target effects require careful evaluation
Future Directions
First-in-human dose-finding studies assessing GDF15/FGF21 pharmacodynamics, tolerability, and weight/metabolic outcomes; exploration of ISR-selective analogs to optimize therapeutic index.
Study Information
- Study Type
- Basic/Preclinical
- Research Domain
- Treatment
- Evidence Level
- V - Animal and mechanistic studies without human clinical outcomes
- Study Design
- OTHER