LIAO Sicong^abc, ZHU Caiyua^bc, WU Huixian^abc, JIN Junfei^abc

(a. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, b. Guangxi HealthCommission Key Laboratory of Basic Research in phingolipid Metabolism Related Diseases,c. China-USA Lipids in Health and Disease Research Center, Affiliated Hospital of Guilin Medical University,Guilin 541001,China)

^{Abstract Objective To explore the role of ferroptosis in the resistance of liver cancer cells to lenvatinib'Lenva), and provide new ideas for preventing or reversing Lenva resistance. Methods Human livercancer cell line PLC/PRF/S cells also known as parental cells ( PC ) were cultured in vitro, and Lenvaresistant cells(LRG)were constructed using gradient concentration induction method. RNA-seqtechnology was used for transeriptome sequencing of LRC and PC. Differential expression gene analysis andKEGG enrichment analysis were completed. Cell viability was measured by CCK-8 assay. Expressions offerroptosis related proteins were detected by Westemn blot. The reactive oxygen species ( ROS) wasdetected using DHE probes, and changes in mitochondrial morphology were observed by transmissionelectron microseopy ( TEM ) . Results 'The half inhibitory concentration IC of Lenva in PC group and LRCgroup was 24.88 pmol/L, and 89.34 pmol/L, respectively, indicating the successful induction of Lenvaresistant human liver cancer cells in vitro. A total of 12 106 genes were detected by RNA-seq, amongwhich 88 genes were upregulated and 197 genes were downregulated in the LRC group compared to the PCgroup. The KEGG pathway enrichment analysis of differential expression genes showed that ferroptosissignaling pathway was enriched within it. Under the exposure of Lenva ( 10 pmol/L, for 48 h), theexpression of ferroptosis related proteins SLC7A11 and GPX4 were increased in the LRC group comparedto the PC group, while the content of ROS was decreased. TEM results showed that compared to the PCgroup, the characteristic mitochondrial morphological changes related to ferroptosis in the LRC group weresignificantly reduced. Conclusion Lenva resistance in liver cancer cells may involve multiple genes andsignaling pathways, among which ferroptosis resistance may be a key role in causing Lenva resistance.}

^{Keywords:lenvatinib;liver cancer: drug resistance; ferroptosis}

^{DOI:10.19296/j.cnki.1008-2409.2024-03-001}

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