Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality globally, with hypoxia recognized as a key factor in its progression. Solute carrier family 27 member 5 (SLC27A5/FATP5), a pivotal enzyme in hepatic fatty acid transport and bile acid metabolism, is frequently downregulated in hepatocellular carcinoma, resulting in poor prognosis. However, the link between hypoxia and the suppression of SLC27A5 in HCC remains to be elucidated. Here, we investigated the hypoxia-induced downregulation of SLC27A5 and its impact on HCC proliferation via the repression of hepatocyte nuclear factor 4 alpha (HNF4A). Utilizing in vitro and in vivo hepatocellular carcinoma models, we have demonstrated that hypoxic conditions significantly reduce SLC27A5 transcription, which is mediated by the suppression of HNF4A. This reduction leads to the activation of the AKT pathway and an increase in cyclin-dependent kinase 2 (CDK2) and Cyclin E1 (CCNE1) expression, promoting the transition from the G1 to S phase of the cell cycle and driving HCC proliferation. Furthermore, we show that the pharmacological activation of HNF4A using Benfluorex, in combination with the AKT inhibitor MK2206, significantly inhibits tumor growth in a subcutaneous MHCC-97H xenograft model, suggesting a synergistic therapeutic potential. Together, our study provides novel insights into the hypoxia-mediated regulatory mechanisms in HCC and highlights the HNF4A/SLC27A5/AKT axis as a promising target for combination therapy.