There is a need for more research to better understand the characteristics of the MONW phenotype, the cause of metabolic dysfunction in the absence of obesity, and evaluate potential therapies so as to facilitate the establishment of clinical guidelines.

We demonstrate that in human HCCs with deregulated expression of purine metabolic enzymes, targeting purine metabolism was effective in blocking tumor cell proliferation, leading to tumor shrinkage. Precise regulation of purine metabolic activity was coordinated by the activation status of a PI3K‐E2F1 axis, and potent suppression of purine metabolism via combinatorial targeting of PI3K and the purine synthetic rate‐limiting enzyme IMPDH resulted in enhanced efficacy in a pre‐clinical model. These data provide a strong basis for future precision‐medicine focused clinical trials targeting this tumor‐specific metabolic adaptation as a point of vulnerability in patients with HCC.