<scp>IRX5</scp> Promoted <scp>SREBP1</scp> ‐Mediated de Novo Fatty Acid Synthesis via <scp>HMGN4</scp> in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), a prevalent malignant tumour, ranks highly in both morbidity and mortality, and its prevention and treatment need further studies. The transcription factor iroquois homeobox 5 (IRX5) plays an essential role in HCC, whereas little is known about its exact functions and underlying mechanisms in tumour metabolism reprogramming. Besides, as a transcription factor that mainly locates in nuclei, IRX5 lacks a nuclear localisation sequence, which makes uncovering the mechanism of IRX5 translocating into the nuclei of great significance. Here, we first found that both IRX5 and HCC development are highly expressed; IRX5 accelerates de novo fatty acid synthesis and promotes cancer cell proliferation and progression. Moreover, the GST pull-down combined with GC/MS experiments identified an interaction between IRX5 and high-mobility group nucleosomal binding domain 4 (HMGN4). Immunofluorescence analysis showed that IRX5 and HMGN4 colocalised within the nucleus. Coimmunoprecipitation further confirmed their direct interaction. The elevated expression of HMGN4 enhanced the nuclear transport of IRX5. Taken together, our observations suggest that HMGN4 driving IRX5 nuclear translocation promotes HCC development via de novo fatty acid synthesis reprogramming.