Unpicking the senescence paradox in MASLD-associated HCC

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Background and context

Patients with MASLD are at risk of progressive liver disease and the development of hepatocellular carcinoma (HCC). In response to chronic injury, hepatocytes can become senescent, a state of cell cycle arrest. The accumulation of senescent hepatocytes correlates with fibrosis stage and predicts adverse clinical outcomes in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).^1,2 Senescent hepatocytes secrete a range of factors (called the senescence-associated

Objectives, methods and findings

In a recent article by Gu et al. in Nature, the authors aimed to address the question of how metabolic dysfunction-associated steatohepatitis (MASH) can simultaneously increase HCC risk whilst inducing replicative senescence in injured hepatocytes.⁶ They focussed on the enzyme fructose-1,6-bisphosphatase 1 (FBP1), a regulator of gluconeogenesis which has been shown to protect against HCC.^7,8 Using immunohistochemistry of an HCC cohort and analyses of large HCC databases, the authors

Significance of findings

This is a complex study which has shed new light on the kinetics of senescent hepatocytes in MASLD and HCC. The data presented results in a proposed model where MASH initially induces cellular stress and DNA damage, leading to FBP1 upregulation, p53 elevation and hepatocyte senescence, which initially prevents propagation of mutations and HCC development. However, in a subpopulation of disease-associated hepatocytes, ongoing stress, alterations in metabolic function and epigenetic modulations

Financial support

P.R. was funded by an MRC Senior Clinical Fellowship (MR/W015919/1).

Conflict of interest

The author of this paper declares that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.