Related Experiment Video
Updated: Jan 7, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Targeting the MIR4435-2HG/miR-29c-3p/FSP1 axis overcomes lenvatinib resistance by inducing ferroptosis in
Congyue Zhang1,2,3, Mengjiao Sun1,2,3, Yue Shi1,2
1Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital, Shijiazhuang, 050051, Hebei Province, China.
Background:
Lenvatinib resistance is a major clinical challenge in advanced hepatocellular carcinoma (HCC). While ferroptosis has emerged as a promising target to overcome therapy resistance, the mechanistic link between ferroptosis and lenvatinib resistance in HCC remains incompletely understood.
Methods:
We analyzed clinical data from TCGA-LIHC and performed functional assays in two HCC cell lines. RNA antisense purification sequencing (RAP-seq) was used to identify downstream targets, and the mechanisms were validated by dual-luciferase reporter assays and Western blotting. Ferroptosis was assessed by measuring lipid reactive oxygen species (lipid ROS) and labile iron levels. Therapeutic efficacy was evaluated both in vitro and in vivo.
Results:
MIR4435-2HG was upregulated in HCC and associated with poorer overall survival. It promoted malignant phenotypes and was further upregulated in lenvatinib-resistant cell lines. Mechanistically, MIR4435-2HG functioned as a competing endogenous RNA (ceRNA) by sponging miR-29c-3p, resulting in upregulation of FSP1. This axis suppressed ferroptosis, thereby conferring lenvatinib resistance. Knockdown of MIR4435-2HG or inhibition of FSP1 synergized with lenvatinib to induce ferroptosis and overcome resistance. The combination strategy significantly suppressed tumor growth in vivo without apparent systemic toxicity.
Conclusion:
Our findings identify a previously uncharacterized MIR4435-2HG/miR-29c-3p/FSP1 axis that promotes lenvatinib resistance by inhibiting ferroptosis, highlighting that targeting this axis may provide a mechanistic basis and preclinical rationale for overcoming lenvatinib resistance in HCC.
Insights
A new MIR4435-2HG/miR-29c-3p/FSP1 pathway drives lenvatinib resistance in liver cancer by blocking ferroptosis. Targeting this axis with lenvatinib overcomes resistance and inhibits tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lenvatinib resistance is a significant clinical hurdle in advanced hepatocellular carcinoma (HCC).
- Ferroptosis presents a potential strategy to overcome therapy resistance in HCC.
- The precise mechanisms linking ferroptosis and lenvatinib resistance in HCC require further elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms underlying lenvatinib resistance in hepatocellular carcinoma.
- To identify novel therapeutic targets for overcoming lenvatinib resistance in HCC.
- To explore the role of ferroptosis in lenvatinib resistance and its potential as a therapeutic target.
Main Methods:
- Analysis of clinical data from TCGA-LIHC and functional assays in HCC cell lines.
- RNA antisense purification sequencing (RAP-seq) to identify downstream targets.
- Assessment of ferroptosis via lipid ROS and labile iron levels, with in vitro and in vivo efficacy evaluation.
Main Results:
- MIR4435-2HG upregulation in HCC correlates with poor survival and promotes malignant phenotypes, notably in lenvatinib-resistant cells.
- MIR4435-2HG acts as a ceRNA for miR-29c-3p, upregulating FSP1, suppressing ferroptosis, and conferring lenvatinib resistance.
- Combined lenvatinib and MIR4435-2HG knockdown or FSP1 inhibition synergistically induced ferroptosis, overcame resistance, and suppressed tumor growth in vivo with minimal toxicity.
Conclusions:
- A novel MIR4435-2HG/miR-29c-3p/FSP1 axis was identified, promoting lenvatinib resistance in HCC by inhibiting ferroptosis.
- Targeting this axis offers a potential therapeutic strategy to overcome lenvatinib resistance in HCC.
- These findings provide a preclinical rationale for combining therapies to target this axis and enhance lenvatinib efficacy in HCC treatment.
More Related Videos
14:51Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
06:38An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
