Preventing liver carcinogenesis through the use of inhibitors targeting metabolic enzymes ACLY, G6PD, and TYMS, combined with 9-cis retinoic acid

The mechanisms that underpin the divergence between hepatocellular carcinoma (HCC) cell proliferation and benign liver regeneration (BLR) remain largely elusive. In this study, a comparative analysis of differentially expressed genes (DEGs) between HCC and BLR was performed. It was found genes pivotal to hepatocellular malignancy and prognosis were conspicuously enriched in metabolic pathways. Strikingly, six metabolic enzymes functioning in regulating biomass synthesis, were upregulated in HCC to serve as attractive therapeutic targets. Conversely, enzymes enriched in retinol metabolism exhibited decreased expression resulting in reduced metabolic intermediate-retinoic acid (RA). Then, enzyme inhibitors and RA were used to assess their synergistic effects in inhibiting HCC cell proliferation. It was found targeting three enzymes, including ATP citrate lyase (ACLY), glucose-6-phosphate dehydrogenase (G6PD), thymidylate synthetase (TYMS), positioned upstream of the biomass synthesis effectively underscored the selective inhibitory effect on HCC cell proliferation, whereas RA exhibited a pronounced tendency to impede HCC cell self-renewal. The conjoint application of these enzyme inhibitors alongside RA achieved a remarkable suppression of HCC cell proliferation. Moreover, this combined regimen was even more potent than sorafenib to thwart tumor growth in vivo. Therefore, combined targeting of these metabolic nodes may offer a potentially efficient strategy for the treatment of HCC.