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The combination of **ebselen** and **sorafenib** is an investigational therapeutic regimen being evaluated for the treatment of hepatocellular carcinoma (HCC). Ebselen, a synthetic organoselenium compound historically known for its antioxidant properties, has been identified as a potent inhibitor of mannose phosphate isomerase (MPI). In the context of aldolase B (ALDOB) deficiency—a common metabolic alteration in HCC—ebselen mimics fructose 1-phosphate (F1P) to competitively bind and inhibit MPI. This inhibition disrupts protein N-glycosylation, triggering maladaptive endoplasmic reticulum (ER) stress and subsequent apoptosis in cancer cells. Sorafenib is an approved small-molecule multikinase inhibitor that targets tumor cell proliferation and angiogenesis. When combined, ebselen and sorafenib exhibit strong synergistic effects, significantly enhancing tumor suppression in preclinical models of primary liver cancer.
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