Steatotic liver disease induces YAP/TAZ-driven cell competition that can suppress tumor initiation

Abstract

Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are leading risk factors for liver cancer. While inflammation and fibrosis are known to promote tumorigenesis in MASH, the role of early MASLD in cancer initiation is unclear. Here, we investigated how steatosis alone, without significant fibrosis and inflammation, influences liver cancer development in mouse models.

Methods: We fed mice a Western diet to induce early-stage MASLD, characterized by steatosis and mild hepatitis without fibrosis, and triggered liver tumorigenesis by hydrodynamic tail vein injection of plasmids encoding oncogenes. We combined this with genetic manipulation of Hippo signaling and assessed tumor development using histology and single-nucleus RNA sequencing.

Results: Western diet suppressed liver tumor development by promoting the elimination of tumor-initiating cells. This effect was not due to a direct impact on oncogene-expressing cells, but rather to increased competitiveness of the surrounding hepatocytes. Mechanistically, the Western diet activated the Hippo pathway effectors Yap and Taz in steatotic hepatocytes, enabling them to outcompete tumor-initiating cells. Progression to advanced MASH abrogated this tumor-suppressing effect, allowing tumor development.

Conclusions: Steatotic hepatocytes in early MASLD activate a Yap/Taz-dependent cell competition program that can suppress tumor initiation. This tumor-suppressive effect is lost in advanced MASH, where inflammation, fibrosis and other defects undermine the competitiveness of non-mutant hepatocytes. The tumor-suppressive effect of early MASLD adds a new layer to our understanding of how fitness landscapes and cell interactions shape cancer risk during chronic liver disease.

Impact and implications: We found that early stages of steatotic liver disease (MASLD) can suppress tumor initiation in mouse models of liver cancer by triggering Yap/Taz-mediated cell competition. This reveals an unexpected tumor-suppressive role for early MASLD and highlights the importance of non-cell autonomous mechanisms during tumor initiation. Since Hippo-YAP/TAZ signaling is deregulated in many cancers, similar mechanisms may operate in other tissues.

Keywords: HCC; Hippo pathway; MASH; MASLD; cell competition; fibrosis; steatosis; tumorigenesis.