ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.