Recently, Advanced Science (IF=15.1), an internationally recognized academic journal, published online the latest research results of the team of Lingyi Kong/Hao Zhang from the School of Traditional Chinese Medicine of the University of China, “Lefamulin Overcomes Acquired Drug Resistance via Regulating Mitochondrial Homeostasis by Targeting ILF3 in Hepatocellular Carcinoma”. Ying Zheng, a PhD student of the College of Traditional Chinese Medicine class of 2022, is the first author of this paper, Prof. Lingyi Kong and Prof. Hao Zhang are the co-corresponding authors of this paper, and China Pharmaceutical University (CPU) is the sole correspondent.
Based on a phenotypic screening model for reversing hepatocellular carcinoma resistance, the team screened a novel natural product derivative of truncated siderophore antibiotic Lefamulin (Lefamulin), a natural product derivative of truncated siderophore antibiotic for reversing hepatocellular carcinoma resistance, from among 1,430 clinically approved small molecule drugs. This study found that Lefamulin overcame tyrosine kinase inhibitors (TKIs, including Sorafenib, Regorafenib, and Lenvatinib) resistance in hepatocellular carcinoma cell lines, xenograft tumor models, and hydrodynamically induced hepatocellular carcinoma models. Further studies revealed that Lefamulin regulates mitochondrial homeostasis and reverses hepatocellular carcinoma resistance by targeting binding to the Ala99 position of ILF3 protein and blocking GCN5/CBP-mediated acetylation of ILF3 Lys100 position, which in turn inhibits ILF3-mediated MRPL12 transcription. This study reveals for the first time the important role of ILF3 as a clinical biomarker of drug resistance in hepatocellular carcinoma, and lays the foundation for the development of innovative drugs and combination therapeutic strategies targeting ILF3.
This work was supported by the National Natural Science Foundation of China (NSFC), the Distinguished Youth Fund of Jiangsu Province, the “Major New Drug Creation and Manufacturing” Science and Technology Special Project, the Fundamental Research Funds of the Central Universities of China, and the 111 Program.
Link: https://onlinelibrary.wiley.com/doi/10.1002/advs.202401789
