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Targeting the SP1/ACSL4 axis attenuates ferroptosis in trastuzumab-induced cardiotoxicity
Qiyuan Hu1, Bincheng Zhong2, Yajie Zheng3
1Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Trastuzumab, a mainstay in treating HER2-positive breast, gastric, and lung cancers, inhibits tumor growth by inducing cell cycle arrest, apoptosis, and anti-angiogenesis. However, its clinical use is limited by cardiotoxicity. This study demonstrates that trastuzumab-induced myocardial injury is mechanistically linked to ferroptosis. Trastuzumab dysregulates key ferroptosis-related proteins (increasing ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) and decreasing SLC7A11 (Solute Carrier Family 7 Member 11) expression), elevating lipid peroxidation levels. Crucially, we screen out the transcription factor SP1 (Sp1 transcription factor) from the public database, regulator of ACSL4. Silencing SP1 significantly attenuates trastuzumab-triggered myocardial ferroptosis. Collectively, our findings establish ferroptosis as the primary pathway underlying trastuzumab-associated cardiotoxicity and propose SP1 inhibition as a promising therapeutic strategy to mitigate this adverse effect.
Insights
Trastuzumab treatment causes heart damage through ferroptosis, a process involving lipid peroxidation. Inhibiting the SP1 transcription factor may prevent this cardiotoxicity, improving cancer treatment safety.
Area of Science:
- Oncology
- Cardiology
- Molecular Biology
Background:
- Trastuzumab is a key therapy for HER2-positive cancers.
- Cardiotoxicity limits Trastuzumab's clinical application.
- The precise mechanism of Trastuzumab-induced cardiotoxicity remains unclear.
Purpose of the Study:
- To elucidate the mechanism underlying Trastuzumab-associated cardiotoxicity.
- To investigate the role of ferroptosis in Trastuzumab-induced myocardial injury.
- To identify potential therapeutic targets for mitigating Trastuzumab cardiotoxicity.
Main Methods:
- Analysis of ferroptosis-related protein expression (ACSL4, SLC7A11) in response to Trastuzumab.
- Assessment of lipid peroxidation levels.
- Identification and manipulation of the transcription factor SP1.
- Silencing SP1 to evaluate its effect on Trastuzumab-induced ferroptosis.
Main Results:
- Trastuzumab treatment induces myocardial injury mechanistically linked to ferroptosis.
- Trastuzumab dysregulates ferroptosis markers, increasing ACSL4 and decreasing SLC7A11 expression, leading to elevated lipid peroxidation.
- The transcription factor SP1 was identified as a regulator of ACSL4 and silencing SP1 significantly reduced Trastuzumab-induced myocardial ferroptosis.
Conclusions:
- Ferroptosis is the primary pathway mediating Trastuzumab-associated cardiotoxicity.
- SP1 is a critical regulator in this process.
- Inhibition of SP1 presents a potential therapeutic strategy to prevent Trastuzumab-induced cardiotoxicity.
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