Lipidation-dimerization platform unlocks treatment potential of fibroblast growth factor 21 for non-alcoholic steatohepatitis

Optimizing the druggability of both native and AI-designed bioactive proteins is crucial for realizing their therapeutic potential. A key focus in designing protein-based therapeutics is improving their pharmacokinetic properties. However, a significant challenge is to preserve biological activity while implementing long-acting strategies. Fibroblast growth factor 21 (FGF21), an endogenous hormone with potential as a treatment for non-alcoholic steatohepatitis (NASH), exemplifies this challenge. In this study, we present a novel lipidation-dimerization (LiDi) platform that integrates lipidation with a dimeric form of FGF21 connected by a hydrophilic linker. The lipidation enhances albumin binding, enabling sustained release, while the dimeric structure boosts biological activity. In vivo evaluations of the LiDi FGF21 analogs demonstrated that they offer excellent pharmacokinetic properties and superior efficacy compared to other treatments for NASH. This platform effectively extends the therapeutic half-life of proteins without compromising their activity, substantially broadening the application range of proteins as therapeutics. [Display omitted] •The lipidation-dimerization (LiDi) platform significantly enhances the sustained release and efficacy of fibroblast growth factor 21 (FGF21).•By optimizing FGF21 through this platform, we achieved remarkable pharmacokinetic properties across different species.•Our studies demonstrated superior therapeutic effects in a model of non-alcoholic steatohepatitis (NASH).•These findings underscore the potential of LiDi FGF21 analogs as effective treatments for managing NASH.