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The effect of inhibiting the cGAS-STING pathway in a chronic liver disease mouse model

ABSTRACT: Hepatocellular carcinoma (HCC) mostly develops on the background of a chronic liver disease (CLD). The hallmarks of CLD includes increased hepatocyte apoptosis, compensatory proliferation and DNA damage. Mice with MCL-1 deficiency in hepatocytes (Mcl-1Dhep mice ) recapitulated these key features of CLD and developed HCC later in life. However, it is unclear how MCL-1 deficiency drives tumorigenesis. We analysed replication stress and the activation the cGAS-STING pathway in Mcl-1Dhep mice. 2-month-old Mcl-1Dhep mice showed increased replication stress, micronucleated hepatocytes and increased cytosolic DNA sensing. We found that an increase in extrachromosomal circular DNA in Mcl-1Dhep liver promoted a crosstalk between hepatocytes and immune cells to drive the immune response which was dependent on the canonical cGAS-STING pathway. We then generated Mcl-1Dhep/STING-/- double knockout mice to study the effects of inhibiting the cGAS-STING pathway in liver homeostasis and tumorigenesis. In fact, deletion of STING in Mcl-1Dhep mice reduced immune cell chemotaxis, as well as tumor incidence. Our findings indicate that the cytosolic DNA sensing pathway may play an important role in inflammation-driven liver carcinogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE277012 | GEO | 2025/09/09

REPOSITORIES: GEO

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