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NRF2 is the master transcriptional activator of cytoprotective genes and Kelch-like ECH-associated protein 1 (Keap1), a biosensor for electrophiles and oxidation, promotes NRF2 degradation in unstressed conditions. SQSTM1/p62, an oncogenic protein aberrantly accumulated in hepatocellular carcinoma (HCC), binds and sequestrates Keap1, leading to the prevention of NRF2 degradation. Here, we show that p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A) is highly expressed in HCC tumors and correlated with aggressive clinicopathological features. RPRD1A competitively interacts with TRIM21, an E3 ubiquitin ligase of p62, resulting in the decrease of p62 ubiquitination and the increased sequestration for Keap1. Therefore, RPRD1A enhances the nuclear translocation of NRF2, which induces gene expression for counteracting oxidative stress, maintaining cancer cells survival, and promoting HCC development. Moreover, disturbing the redox homeostasis of cancer cells by genetic knockdown of RPRD1A sensitizes cancer cells to platinum-induced cell death. Our study reveals RPRD1A is involved in the oxidative stress defense program and highlights the therapeutic benefits of targeting pathways that support antioxidation.

RPRD1A stabilizes NRF2 and aggravates HCC progression through competing with p62 for TRIM21 binding