Wang Zhuo, Yang Yang, Yao Fang-Ting, Zhang Feng, Lin Ke-Ying, Diao Hong-Tao, Zhao Qiao-Yue, Kong Xue, Si Wei, Xie Ya-Ting, Song Jing-Lun, Zeng Ling-Hua, Wang Chun-Lei, Xiong Yu-Ting, Zou Kun-Kun, Wang Xiao-Man, Zhang Xin-Yue, Wu Han, Jiang Wei-Tao, Bian Yu, Yang Bao-Feng
College of Traditional Chinese Medicine and Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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.
Acta Pharmacol Sin. 2025 Mar 27. doi: 10.1038/s41401-025-01528-4.
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.
肝癌是一种侵袭性很强的恶性肿瘤，生存率很低。目前的治疗方法，包括肝移植、免疫疗法和基因疗法，常常受到晚期诊断和严重副作用的限制，这凸显了对新型治疗药物的迫切需求。在本研究中，我们评估了新型蒽醌衍生物康乐欣（KLX）在肝癌治疗中的治疗潜力。在体外，KLX以剂量依赖性方式抑制HepG2和Hep3B细胞的增殖和迁移。机制上，KLX上调Z-DNA结合蛋白1（ZBP1）的表达，通过直接与ZBP1结合、改变其构象并降低其对E3泛素连接酶环指蛋白180（RNF180）的亲和力来诱导PAN细胞焦亡。这种相互作用减少了ZBP1的泛素化，从而增加了其稳定性。此外，KLX上调转录因子同源盒D10（HOXD10）的表达，进而进一步增加ZBP1的表达。ZBP1水平升高显著抑制肝癌细胞的增殖和迁移，而在ZBP1基因敲低后，KLX的抑制作用被逆转。在异种移植模型中，KLX显著抑制肿瘤生长，且毒性低于奥沙利铂（OXA）。总之，KLX通过上调ZBP1并防止其降解来促进肝癌细胞的PAN细胞焦亡，从而抑制肝癌的进展和迁移。这些发现表明KLX是一种有前途的肝癌治疗药物。
