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

作者：Zhuo Wang, Yang Yang, Fangyin Yao, Feng Zhang, Ke-ying Lin, Hongtao Diao, Qiao-yue Zhao, Xue Kong, Si Wei, Yating Xie, Jing-lun Song, Lisi Zeng, Wang Chun-lei, Yu-ting Xiong, Kun Zou, Xiaoman Wang, Xinyue Zhang, Han Wu, Weitao Jiang, Yu Bian, Baofeng Yang · 发表于：Acta Pharmacologica Sinica · 年份：2025 · DOI：10.1038/s41401-025-01528-4 · 被引用次数：5 · 研究领域：Bioactive Compounds and Antitumor Agents、ATP Synthase and ATPases Research、Natural product bioactivities and synthesis

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 thera...