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Fibroblast growth factor 21 (FGF21) is a master regulator of metabolism associated with positive outcomes in a variety of metabolic disorders including metabolic-dysfunction associated steatohepatitis (MASH). In animal models of chronic liver disease, FGF21 has been shown to be protective against development and progression of hepatocellular carcinoma (HCC). We investigated in human in vitro models of pre-cancerous MASH and MASH-HCC the impact of FGF21 on gene expression of a variety of HCC associated genes.Human adult stem cell derived hepatic organoids (HO) and HCC cell line HepG2 were stimulated with tumour necrosis factor α (TNFα) 25 ng/ml, lipopolysaccharide (LPS) 100 ng/ml and palmitic acid (PA)-BSA 0.5 mM (HO) or 0.25 mM (HepG2) for 24 hours to recapitulate the MASH environment in a pre and established HCC model respectively. As expected, PA, LPS and TNFα elicited a significant increase in CXCL8 gene expression 47.52 ± 26.00 (HO) and 10.15 ± 2.05 (HepG2), validating the models. PA, LPS and TNFα was associated with increased gene fold expression of TP53 1.69 ± 0.19, MKI67 1.87 ± 0.29 and HIF1A 1.95 ± 0.14 and decreased in CDH1 0.64 ± 0.09 in hepatic organoids, which resolved with the addition of rFGF21 in TP53 0.95 ± 0.20 and MKi67 0.7825 ± 0.11. In the HepG2 MASH model, PA, LPS and TNFα stimulation led to increase in gene fold expression of CTNNB1 2.35 ± 0.29 and AXIN2 1.93 ± 0.21, both resolving with addition of rFGF21 CTNNB1 1.46 ± 0.15 and AXIN2 1.01 ± 0.12.We demonstrate that expression of cancer related genes change in both in vitro pre-cancerous and cancerous human MASH-HCC models and FGF21 had the ability to reverse many of these. This suggests FGF21 may be protective against development of and progression of HCC in MASLD in humans.