Hepatocellular carcinoma (HCC) represents a significant global health challenge with alarmingly low five-year survival rates and a troubling increase in incidence, particularly associated with obesity-related chronic inflammation and liver damage. Addressing this urgent need for improved diagnostics and treatments, our research focuses on identifying cancer cell-specific nutritional dependencies that can be targeted through innovative dietary and pharmacological interventions. We discovered that liver tumors exhibit a heightened uptake of the essential amino acid tryptophan (Trp), leading to a remarkable dependency on Trp for growth. By introducing a synthetic diet lacking Trp, termed "...

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Hepatocellular carcinoma (HCC) represents a significant global health challenge with alarmingly low five-year survival rates and a troubling increase in incidence, particularly associated with obesity-related chronic inflammation and liver damage. Addressing this urgent need for improved diagnostics and treatments, our research focuses on identifying cancer cell-specific nutritional dependencies that can be targeted through innovative dietary and pharmacological interventions. We discovered that liver tumors exhibit a heightened uptake of the essential amino acid tryptophan (Trp), leading to a remarkable dependency on Trp for growth. By introducing a synthetic diet lacking Trp, termed "Trypt-out," we achieved complete inhibition of tumor growth in mouse models. Surprisingly, this inhibition occurs through a translation-independent mechanism, highlighting the potential of dietary interventions in cancer therapy. Furthermore, we identified the Trp metabolite indole-3-pyruvate (I3P) as the sole metabolite capable of rescuing liver tumor growth in mice fed the Trypt-out diet. Elevated levels of I3P and the enzyme IL4I1, responsible for converting Trp into I3P, were observed in mouse liver tumors, suggesting a specific oncogenic role for Trp via I3P. Our research aims to validate the I3P pathway as a biomarker for HCC, test strategies to inhibit IL4I1 to prevent liver cancer growth, and investigate the roles of Trp, I3P, and IL4I1 in obesity-related HCC growth. By unraveling the mechanisms underlying I3P's function as an oncometabolite, we aim to develop I3P as a novel biomarker for improved disease staging and a target for more precise therapy.

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