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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.
Abstract:
The TKI-targeted agent lapatinib has been applied in clinical oncology for the management of multiple malignancies. Nonetheless, its therapeutic benefit is restricted by cardiotoxic effects that endanger patient survival, and the underlying molecular basis remains unclear. The GSE146096 dataset containing transcriptomic profiles of lapatinib-exposed human cardiomyocytes was analyzed to identify ferroptosis-related differentially expressed genes (DEGs). Protein expression of selected targets was subsequently confirmed by Western Blot. Reactive oxygen species (ROS) accumulation, Fe²⁺ levels, and mitochondrial membrane potential in AC16 cells exposed to lapatinib were examined using confocal microscopy. A microplate reader was employed to quantify alterations in malondialdehyde (MDA) and glutathione (GSH) levels in cardiomyocytes. Eight ferroptosis-associated genes were identified in lapatinib-treated cardiomyocytes, including the canonical regulator GPX4. siRNA interference and Western Blot analyses demonstrated marked induction of ATF4 expression and significant suppression of GPX4 expression following lapatinib exposure in AC16 cells. CCK-8 assays indicated dose-dependent cytotoxicity. Confocal microscopy and transmission electron microscopy (TEM) revealed altered mitochondrial morphology accompanied by a reduction in mitochondrial membrane potential. Intracellular MDA levels increased substantially, whereas GSH levels declined, indicating lipid peroxidation and subsequent ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or silencing of ATF4 expression effectively attenuated lapatinib-induced cytotoxicity. Lapatinib enhances ATF4 expression in cardiomyocytes, suppresses GPX4, triggers lipid peroxidation, induces ferroptosis, and thereby contributes to cardiotoxicity.
Insights
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.
