Targeting ornithine aminotransferase as a promising therapeutic strategy for hepatocellular carcinoma

Comprising 90% of all liver cancers, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Despite decades of research, prognosis remains poor: approximately 800,000 people are diagnosed with HCC each year, and ~80% die within five years. Therapeutically, there is a critical unmet need for more effective treatments. Resistance to sorafenib, the current first-line multi-target tyrosine kinase inhibitor, has become increasingly common. Moreover, more than 150 clinical trials evaluating targeted agents, immunotherapies, and combination regimens have failed due to insufficient efficacy, underscoring the urgent need for novel, mechanism-based therapeutic strategies. Emerging evidence highlights the central role of metabolic reprogramming in carcinogenesis, treatment resistance, and recurrence across multiple cancers, including HCC. Ornithine aminotransferase (OAT) is a key enzyme in this process, linking amino acid metabolism, particularly glutamine and proline, to polyamine biosynthesis and cancer cell proliferation. OAT is overexpressed in HCC and validated as a therapeutic target in preclinical models. We previously demonstrated that the OAT inactivator LHJ-2-79 effectively inhibits tumor growth in HepG2 and Hep3B xenografts and significantly suppresses alpha-fetoprotein (AFP) secretion, a key HCC biomarker, in Hep3B and HepG2 cells. However, no OAT inactivators have yet advanced to clinical trials. To address this gap, our laboratory recently synthesized SS-1-148, a novel OAT inactivator. Here, we report the effects of SS-1-148 on HCC using IC50 profiling, enzyme expression assays, xenograft survival studies, RNA-seq analysis, and metabolomic data. Our findings reveal cell line-dependent differences in SS-1-148 potency, OAT activity inhibition, tumor growth suppression, metabolic gene expression, and alterations in proline and polyamine levels. In vivo, SS-1-148 inhibited Huh-7 xenograft growth but not Huh-6 tumors. Metabolomic analyses of LHJ-2-79 and SS-1-148 in Huh-6 and Huh-7 cells further demonstrated distinct effects on proline and putrescine levels, suggesting different mechanisms of action between the two inactivators. Collectively, these results support OAT as a promising therapeutic target in HCC and lay the foundation for further development of OAT-based treatment strategies.