2. Academic Validation
  3. KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis

KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis

  • Acta Pharmacol Sin. 2025 Aug;46(8):2282-2295. doi: 10.1038/s41401-025-01528-4.
Zhuo Wang # 1,  Yang Yang # 2,  Fang-Ting Yao # 2,  Feng Zhang 2,  Ke-Ying Lin 2,  Hong-Tao Diao 2,  Qiao-Yue Zhao 2,  Xue Kong 2,  Wei Si 2,  Ya-Ting Xie 2,  Jing-Lun Song 2,  Ling-Hua Zeng 2,  Chun-Lei Wang 2,  Yu-Ting Xiong 2,  Kun-Kun Zou 2,  Xiao-Man Wang 2,  Xin-Yue Zhang 2,  Han Wu 2,  Wei-Tao Jiang 2,  Yu Bian 3,  Bao-Feng Yang 4 5
Affiliations

Affiliations

  • 1 College of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 2 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 3 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. bianyu@hrbmu.edu.cn.
  • 4 College of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. yangbf@ems.hrbmu.edu.cn.
  • 5 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. yangbf@ems.hrbmu.edu.cn.
  • # Contributed equally.
PMID: 40148674 DOI: 10.1038/s41401-025-01528-4
Abstract

Liver Cancer is a highly aggressive malignancy with poor survival rates. Current treatments, including liver transplantation, immunotherapy, and gene therapy, are often limited by late-stage diagnosis and significant side effects, highlighting the urgent need for novel therapeutic agents. In this study, we evaluated the therapeutic potential of Kanglexin (KLX), a novel anthraquinone derivative, in the treatment of liver Cancer. In vitro, KLX inhibited the proliferation and migration of HepG2 and Hep3B cells in a dose-dependent manner. Mechanistically, KLX upregulated Z-DNA binding protein 1 (ZBP1) expression, inducing PANoptosis by directly binding to ZBP1, altering its conformation, and reducing its affinity for the E3 ubiquitin Ligase ring finger protein 180 (RNF180). This interaction decreased ZBP1 ubiquitination, thereby increasing its stability. Additionally, KLX upregulated the expression of the transcription factor homeobox D10 (HOXD10), which further increased ZBP1 expression. Elevated ZBP1 levels significantly suppressed liver Cancer cell proliferation and migration, whereas the inhibitory effects of KLX were reversed upon ZBP1 knockdown. In a xenograft model, KLX significantly inhibited tumor growth with a lower toxicity than oxaliplatin (OXA). In conclusion, KLX promoted PANoptosis in liver Cancer cells by upregulating ZBP1 and preventing its degradation, thereby inhibiting liver Cancer progression and migration. These findings suggest that KLX is a promising therapeutic agent for liver Cancer.

Keywords

HOXD10; Kanglexin; PANoptosis; ZBP1; anthraquinone; liver cancer.

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