The CCR5/ROS/NRF2 axis Mediates Dihydrotanshinone I-Induced oxidative stress and apoptosis in hepatocellular carcinoma

  • Biochem Pharmacol. 2025 Jul 7:241:117119. doi: 10.1016/j.bcp.2025.117119.
Ruoxin Tu  1 ,  Yining Wang  2 ,  Ru Xu  1 ,  Shusheng Wang  1 ,  Jiabin Cai  3 ,  Lin Sun  4 ,  Pengfei Gao  5
Affiliations
  • 1. Department of Traditional Chinese Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.
  • 2. Department of Neurosurgery, National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, China.
  • 3. Department of Liver Surgery and Transplantation, Zhongshan Hospital (Xiamen), Fudan University, China.
  • 4. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Branch of National Clinical Research Center for Laboratory Medicine, Shanghai, China. Electronic address: [email protected].
  • 5. Department of Traditional Chinese Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China. Electronic address: [email protected].
PMID: 40633809 DOI: 10.1016/j.bcp.2025.117119
Abstract

Despite therapeutic advances, hepatocellular carcinoma (HCC) remains a leading cause of Cancer mortality worldwide. While dihydrotanshinone I (DHT) shows promising Anticancer potential, its molecular mechanisms in HCC remain unexplored. Here, we unveil a novel chemokine (C-C motif) receptor 5 (CCR5)-mediated regulatory network targeted by DHT in HCC treatment. This study identifies CCR5 as a crucial survival factor in HCC, uncovers a novel CCR5-nuclear factor erythroid 2-related factor 2 (NRF2) regulatory axis, and reveals a dual-targeting mechanism of DHT through direct CCR5 inhibition and Reactive Oxygen Species (ROS)-dependent cell death induction, validating its therapeutic efficacy by disrupting redox homeostasis. This work uncovers a novel CCR5-ROS-NRF2 signaling axis in HCC and establishes DHT as a promising therapeutic agent through its unique targeting mechanism. These findings provide new insights into HCC pathogenesis and present an innovative therapeutic strategy for HCC treatment.

Keywords
CCR5/ROS/NRF2; Dihydrotanshinone I; Hepatocellular carcinoma; Oxidative stress.
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