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Lapatinib Induces Ferroptosis in Cardiomyocytes by Regulating ATF4/GPX4
Yue Sun1,2, Keyi Jiang1,2, Dan Wang1,2
1Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
Cardiovascular Toxicology
|July 24, 2026
Summary
Lapatinib causes cardiotoxicity by inducing ferroptosis in heart cells. This involves increased oxidative stress, reduced GPX4, and lipid peroxidation, which can be blocked by ferroptosis inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiology
Background:
- Lapatinib, a tyrosine kinase inhibitor (TKI), is used in oncology but causes cardiotoxicity.
- The molecular mechanisms underlying lapatinib-induced cardiotoxicity are not fully understood.
Purpose of the Study:
- To investigate the role of ferroptosis in lapatinib-induced cardiotoxicity.
- To identify molecular targets and pathways involved in lapatinib's cardiac side effects.
Main Methods:
- Analysis of transcriptomic data (GSE146096) from lapatinib-exposed cardiomyocytes.
- Validation of gene and protein expression (ATF4, GPX4) using Western Blot and siRNA.
- Assessment of cellular markers of ferroptosis, including ROS, Fe²⁺, mitochondrial potential, MDA, and GSH levels.
- Evaluation of cytotoxicity using CCK-8 assays and protective effects of Ferrostatin-1.
Main Results:
- Eight ferroptosis-related genes, including GPX4, were differentially expressed in lapatinib-treated cardiomyocytes.
- Lapatinib induced ATF4 expression and suppressed GPX4, leading to lipid peroxidation and ferroptosis.
- Mitochondrial dysfunction and reduced membrane potential were observed.
- Ferrostatin-1 or ATF4 silencing mitigated lapatinib-induced cytotoxicity.
Conclusions:
- Lapatinib triggers cardiotoxicity by upregulating ATF4, downregulating GPX4, and inducing ferroptosis in cardiomyocytes.
- Targeting ferroptosis pathways may offer a therapeutic strategy to mitigate lapatinib-induced cardiac damage.
