Targeting the SP1/ACSL4 axis attenuates ferroptosis in trastuzumab-induced cardiotoxicity

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.