Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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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.