Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.
Background Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo . To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . Methods Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Findings Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo . One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. Interpretation This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. Funding HEC Pharm R&D Co., Ltd, National natural science fund of China.
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