KEAP1 Dysregulation in Hepatocellular Carcinoma: Functional Characterization and Therapeutic Targeting

Abstract

Hepatocellular Carcinoma (HCC), the most prevalent primary liver cancer, remains a global health challenge due to its aggressive biology and limited therapeutic options. Kelch-like ECH-associated protein 1 (KEAP1), a critical regulator of the NRF2 antioxidant pathway, has emerged as a key player in HCC pathogenesis. This comprehensive study employs in vitro, ex vivo, and in vivo models
to investigate the functional consequences of KEAP1 dysregulation in HCC, focusing on tumor cell proliferation, migration, chemoresistance, and immune microenvironment modulation. Through siRNA-mediated knockdown, CRISPR-Cas9 genome editing, and pharmacological interventions, we demonstrate that KEAP1 deficiency promotes oncogenic phenotypes via NRF2 hyperactivation, while also inducing metabolic reprogramming and immune evasion. Clinical correlation analyses using TCGA-LIHC dataset and tissue microarrays further validate the prognostic significance of KEAP1 expression in HCC patients. Our findings establish KEAP1 as a multifunctional oncogenic driver and highlight the therapeutic potential of targeting the KEAP1-NRF2 axis in HCC, particularly in overcoming chemoresistance and enhancing immunotherapeutic responses.