What question did this study set out to answer?

The aim is to investigate the effects of MST3 inhibition on metabolic dysfunction and its link to liver cancer in mice.

March 26, 2026Open Access

Targeting STE20-type kinase MST3 improves metabolic dysfunction-associated steatohepatitis without affecting hepatocellular carcinoma development in mice

Key Points

The aim is to investigate the effects of MST3 inhibition on metabolic dysfunction and its link to liver cancer in mice.
Induced MASH-HCC in a mouse model using diethylnitrosamine and a Western-style diet.
Assessed liver tumor burden at various time points after treatment with MST3-targeting antisense oligonucleotides (ASO).
Conducted proteomic profiling on MST3 knockout and wild-type cells to understand molecular pathways.
Mst3 ASO therapy improved metabolic profile but did not affect the onset of MASH-associated HCC.
Showed suppression of all key features associated with MASH.
Proteomic analysis indicated activation of mitochondrial and lysosomal pathways in MST3-deficient cells, suggesting improved fatty acid degradation.

Abstract

Abstract Background Metabolic dysfunction-associated steatohepatitis (MASH) is a major precursor of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking steatohepatitis to malignancy remain poorly defined. The STE20-type kinase MST3 associates with hepatocellular lipid droplets and regulates metabolic homeostasis and stress responses in the liver. Here, we investigated whether pharmacologic inhibition of MST3 could attenuate the initiation and progression of MASH-associated HCC in vivo. Methods The therapeutic potential of MST3 inhibition was evaluated in a mouse model in which MASH-HCC was induced by a single diethylnitrosamine injection followed by 30 weeks of Western-style diet feeding. Liver tumor burden was assessed after 12, 21, or 30 weeks of treatment with Mst3 -targeting antisense oligonucleotide (ASO) or a non-targeting control ASO, and histological, biochemical, and mechanistic analyses were performed in the 30-week cohort. In parallel, proteomic profiling of CRISPR/Cas9-generated MST3 knockout and wild-type Huh7 cells was conducted to gain molecular insight into MST3-regulated pathways. Results Mst3 ASO therapy had no impact on the onset or aggravation of experimentally induced MASH-associated HCC in mice, despite markedly improving the whole-body metabolic profile and suppressing all key features of MASH. Proteomic profiling of MST3-deficient hepatocytes revealed coordinated activation of mitochondrial and lysosomal pathways, consistent with enhanced fatty acid degradation and catabolic clearance. Conclusions Our findings in the selected mouse model of MASH-HCC suggest that MST3 is dispensable for hepatocarcinogenesis, yet its antagonism dampens diet-induced metabolic dysfunction and effectively attenuates MASH severity, challenging the prevailing assumption that targeting MASH driver genes alone is sufficient to prevent HCC development in the context of obesity.

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