Abstract

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and despite advances in systemic therapies, resistance to targeted therapies such as Sorafenib significantly limits clinical benefit and contributes to poor outcomes. The mechanisms that enable HCC cells to withstand oxidative stress and evade therapy remain incompletely understood. Here, we identify an RNA regulatory role of NAT10 in sustaining redox homeostasis in HCC. We show that NAT10 stabilizes Nrf2 mRNA, a master regulator of antioxidant responses, thereby maintaining Nrf2 protein abundance and reducing intracellular reactive oxygen species (ROS) levels in HCC cells. Genetic silencing or pharmacologic inhibition of NAT10 disrupts this regulatory axis, leading to elevated ROS accumulation, induces DNA damage, and enhances apoptosis. Importantly, NAT10 knockdown markedly sensitizes HCC cells to Sorafenib, and simultaneous inhibition of NAT10 and Nrf2 exhibits a synergistic pro-apoptotic effect, suggesting that oxidative stress overload is a key vulnerability created by targeting this pathway. Together, these finding uncover a NAT10-Nrf2 RNA stability axis that enhances antioxidant capacity and therapeutic tolerance in HCC, and highlight NAT10 as a promising target for overcoming drug resistance and improving treatment response.