Discovery of a Biased Kelch-like ECH-Associated Protein 1–p62 (Keap1–p62) Protein–Protein Interaction (PPI) Inhibitor for the Management of p62 Aberrant Hepatocellular Carcinoma

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pleiotropic transcription factor essential for cellular defense. Extensive research has demonstrated its oncogenic role, positioning Nrf2 as a promising target for cancer therapy. However, achieving tumor-specific Nrf2 inhibition remains a challenge. Herein, we report the discovery of 13, a biased inhibitor of Kelch-like ECH-associated protein 1–phosphorylated p62 (Keap1–p-p62) interaction, as a selective and effective Nrf2 inhibitor. In fluorescence polarization assays, 13 showed potent Keap1–p-p62 inhibitory activity (IC50 = 0.11 μM) and high selectivity over the inhibition of Keap1–Nrf2 interaction. Notably, 13 specifically inhibited Nrf2 activity in p62 aberrant hepatocellular carcinoma (HCC) cells by selectively disrupting Keap1–p-p62 interaction and normalizing Nrf2 ubiquitination. Furthermore, cotreatment with 13 sensitized p62 aberrant HCC to ferroptosis induced by sorafenib (TGI = 95.3%). Overall, our study identifies a biased Keap1–p-p62 inhibitor 13 as a targeted Nrf2 inhibition therapy and provides valuable insights into HCC treatment.