Targeting fibroblast growth factor (FGF)-21: a promising strategy for metabolic dysfunction-associated steatotic liver disease treatment

Abstract

Metabolic dysfunction-associated steatitic liver disease (MASLD) is the predominant chronic liver disease, with its incidence increasing year by year. It has emerged as the most rapidly increasing contributor to liver-related mortality worldwide and is becoming a principal cause of end-stage liver disorders, primarily cancer of the liver and liver transplantation, hence putting a substantial economic burden on public health. The approval of Resmetirom signifies significant advancement in the treatment of metabolic dysfunction-associated steatohepatitis (MASH); nonetheless, the heterogeneity of MASLD renders it challenging for a single medication to address the requirements of all patients. Consequently, it is essential to formulate varied therapeutic approaches for distinct pathogenic causes and phases of disease. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factor family, plays a positive and protective role in MASLD. It attenuates hepatic steatosis and lipotoxicity, ameliorates insulin resistance (IR), reduces oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, as well as possesses anti-fibrotic effects. As a result, FGF21 has the potential to treat MASLD. In this review, we will address the possible mechanisms of FGF21 therapy for MASLD to facilitate the development of clinical therapies targeting FGF21 for MASLD.

Keywords: FGF21 analogs; fibroblast growth factor 21; liver fibrosis; metabolic dysfunction-associated steatitic liver disease; metabolic dysfunction-associated steatohepatitis.

FIGURE 1

FGF21 attenuates hepatic steatosis and lipotoxicity (Created with BioRender.com). Abbreviations: DNL, De novo lipogenesis; FA β-oxidation, Fatty acids β-oxidation; FASN, fatty acid synthase; FGFR1, Fibroblast growth factor receptor 1; FGF21, Fibroblast growth factor 21; KLB, β-Klotho; LCN2, Lipocalin-2; Nur77, Orphan nuclear receptor 4A1; p-Nur77, Phospho-Nur77; SCD1, Stearoyl-CoA desaturase-; SBK1, Src homology three domain binding kinase 1; SREBF1, Sterol regulatory element-binding protein 1.

FIGURE 2

FGF21 improves insulin resistance (Created with BioRender.com). Abbreviations: BAT, Brown adipose tissue; JNK, C-Jun N-terminal kinase; mTORC1, Rapamycin complex; TSC1, Tuberous sclerosis complex 1; UCP1, Uncoupling protein 1; WAT, White adipose tissue; XBP1, X-box binding protein 1.

FIGURE 3

FGF21 regulates cellular stress (Created with BioRender.com). Abbreviations: AMPK, AMP-activated protein kinase; GSH, Glutathione; PGC-1α, Peroxisome proliferator-activated receptor γ coactivator-1α; SIRT1, Silent information regulator; SOD, Superoxide dismutase.

FIGURE 4

FGF21 reduces inflammation (Created with BioRender.com). Abbreviations: IL-17A, interleukin-17A; IL-18, interleukin-18; KCs, Kupffer cells; LDLR, Low density lipoprotein receptor; MoKCs, monocyte-derived Kupffer cells; NF-κB, Nuclear factor-kappa B.

FIGURE 5

FGF21 reduces liver fibrosis (Created with BioRender.com). Abbreviations: α-SMA, α-smooth muscle actin; AKT, Protein kinase B; HSCs, Hepatic stellate cells; NR4A1, Nuclear receptor subfamily four group A member 1; Ly6C, Lymphocyte antigen 6C; SOCS3, Suppressor of cytokine signaling 3; STAT3, Signal transducer and activator of transcription 3; TGF-β, Transforming growth factor-β.