Targeting NOTCH1-KEAP1 axis retards chronic liver injury and liver cancer progression via regulating stabilization of NRF2

作者：Chunxiao Chang, Meng Wang, Jia Li, S. Qi, Xiaojuan Yu, Jun Xu, Shengbin Shi · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03488-3 · 被引用次数：4 · 研究领域：Ferroptosis and cancer prognosis、Genomics, phytochemicals, and oxidative stress、FOXO transcription factor regulation

BACKGROUND: Chronic liver injury is a key factor in diseases like hepatocellular carcinoma (HCC), steatohepatitis (NASH), and viral hepatitis type B and C (HBV, HCV). Understanding its molecular mechanisms is crucial for effective treatment. The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target. METHODS: Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc. RESULTS: The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Crucially, we discovered that hepatocyte-specific NOTCH1 knockout reduces hepatocellular damage in chronic liver inflammation and HCC mouse models, whereas adeno-associated virus serotype 8 (AAV8)-mediated NOTCH1 overexpression in hepatocytes exacerbates liver injury-related phenotype on-setting. Mechanistically, we showed that NOTCH1 has a new role in controlling ferroptosis and oxidative damage in hepatocytes. It interacts with Kelch-like ECH-associated protein 1 (KEAP1) and is directly recruited through its intracellular domain (NICD1). Additionally, the KEAP1 recruited by NOTCH1 impeded the binding stability of KEAP1-NFE2 like BZIP transcription factor 2 (Nrf2), promote the s...