Influence of a Zombie-like State of the Liver on Drugs and Its Medico-Legal Implications: A Scoping Review

Abstract

When cells remain permanently trapped in a particular cell cycle stage, they are in senescence. This also occurs in the liver. Such cells are often referred to as "zombie cells", and an entire organ filled with these "zombie cells" is said to be in a "zombie-like" state, characterized by a lack of function. The senescence-associated secretory phenotype (SASP) encompasses the substances these "zombie cells" release, which can significantly affect nearby cells and tissues. While cellular senescence and SASP are related concepts, they are distinct. This scoping review aims to clarify the role of hepatocyte senescence and hepatocyte SASP in the administration of pharmaceuticals, as well as their relevance to medico-legal practice, disability claims, and insurance coverage. In this context, the effects of pharmaceuticals on senescent hepatocytes are discussed, particularly regarding the medico-legal implications of substances likely to be abused. In conclusion, hepatocyte senescence may be relevant in clinical or medico-legal work because it sheds a new light on interpreting clinical findings and expert witness statements.

Keywords: hepatocyte senescence; hepatocyte senescence-associated secretory phenotype (hepatocyte SASP); medico-legal; pharmaceuticals; substances of abuse.

Figure 1

Search strategy identified 167 studies, 27 of which were primary studies. This strategy was based on the guidelines from the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) version PRISMA 2020.

Figure 2

Gene expression data from The Human Protein Atlas© (available at https://www.proteinatlas.org/, accessed on 15 April 2025) are presented in terms of transcripts per million (nTPM) across six age groups: 20–29 years, 30–39 years, 40–49 years, 50–59 years, 60–69 years, and 70–79 years. Focusing on hepatocyte gene expression, two genes traditionally associated with senescence—CDKN1A and IL-6—showed significant differences in expression between the various age groups. The Tukey–Kramer test indicated a significant difference (p = 0.04) when comparing CDKN1A expression between the 20–29 and 60–69 age groups. Significant differences were also seen when comparing the 20–29 age group with the 40–49 age group and each subsequent age group. For comparisons involving three age groups, starting with the 40–49 age group, the p-value for gene expression means was found to be less than 0.01. Additionally, the 70–79 age group demonstrated a significant difference (p = 0.012) compared to the 20–29 age group.