S-adenosylhomocysteine hydrolase (AHCY) catalyzes the hydrolysis of S-adenosylhomocysteine (SAH) to Adenosine (Ado) and Homocysteine (Hyc). Recently, several studies pointed out connections of AHCY with cancer from various standpoints: as a player that possibly regulates cancer phenotype, as a druggable candidate, or, as a promising biomarker. Metabolome-wise, connections between adenosine and cancer have been established, showing stimulative effects on cell proliferation, and other important roles in inflammation or immunity. Implications of AHCY in hepatic pathology are well documented, and culminated in the recently reported case of hepatocellular carcinoma in an adult with AHCY deficiency. Also, as we have preliminary data showing that low AHCY activity and depletion of adenosine induces DNA damage and cell cycle arrest in hepatocellular carcinoma cells. In summary, involvement of AHCY in molecular mechanisms of cancer is undisputable. However, the molecular basis for the connection between AHCY and cancer is not quite obvious. In order to answers these questions we will deploy a multi-omics approach, in combination with basic molecular and cellular biology procedures focus on the role of AHCY and its mechanism of action on cell cycle, cellular proliferation and DNA damage response in histological and serum samples of liver disease patients, in relevant cancerous and AHCY deficient cell lines, and a unique mouse animal model. In particular, we will investigate the implications of adenosine, besides homocysteine, the primary product of AHCY hydrolytic activity on the cellular metabolism. By answering these questions we hope to establish the mechanism that connects AHCY activity, DNA damage and regulation of cell cycle through adenosine levels. The outcomes of underlying research may lead to a refinement of therapeutical procedures for cancer as a result of AHCY malfunction, and a potentially new approach for targeted cancer therapy based on adenosine depletion.