Novel FGF21 analogues through structure-based optimization for therapeutic development

• Structure-based optimization identified P119R and H125R mutations that enhance FGF21 activity approximately twofold. • Fc fusion of these mutants significantly improves pharmacokinetic profile, enabling long-acting therapeutic potential. • The engineered Fc-FGF21 analogs show promise for treating obesity-related metabolic disorders. • This study provides a novel strategy for developing next-generation FGF21-based therapies.