METTL9-SLC7A11 axis promotes hepatocellular carcinoma progression through ferroptosis inhibition

Methytransferase-like proteins 9 (METTL9) has been characterized as an oncogene in several cancers, however, its role in hepatocellular carcinoma (HCC) remains unknown. Here, we investigated the function and molecular mechanism of METTL9 in HCC. We showed that METTL9 expression was elevated in HCC, and its high expression was associated with poor survival outcomes. Knockdown of METTL9 observed a significant inhibition of HCC cell viability, migration, and invasion both in vitro and in vivo. By contrast, METTL9 overexpression HCC cells obtained stronger abilities in cell proliferation and migration. Mechanistically, we discovered that METTL9 knockdown led to a reduction in the expression level of SLC7A11, a key suppressor of ferroptosis, in turn, promoted ferroptosis in HCC cells, impeding the progression of HCC. Moreover, we have proved that targeting METTL9 could significantly restrain the growth of HCC patient-derived xenograft (PDX). Our study established METTL9 as a critical role in promoting HCC development and provides a foundation for further investigation and potential therapeutic interventions targeting ferroptosis in HCC.