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Trastuzumab (TRZ), a monoclonal antibody targeting the ErbB2 protein, significantly improves the prognosis of patients with ErbB2-positive breast or gastric cancer; however, its cardiotoxicity substantially limits its clinical applicability in certain patient populations. TRZ-induced cardiotoxicity (TIC) primarily arises from ErbB2 signaling blockade, compromising cardiomyocyte repair mechanisms and functional integrity. This inhibition further compromises the cellular antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and triggering a cascade of downstream events, including apoptosis, inflammatory responses, ferroptosis, autophagy dysfunction, and pyroptosis. Based on the aforementioned mechanisms, researchers have conducted in-depth investigations into the molecular pathways involved in TIC. To date, decades of research have identified several keys signaling pathways implicated in TIC, including PI3K/Akt, MAPK, STATs, AMPK, mTOR, MDM2/p53, NLRP3, and NF-κB. Furthermore, a number of potential therapeutic agents targeting key molecules in TIC have been explored. However, these findings have not yet been summarized. Therefore, this review aims to comprehensively consolidate existing knowledge on TIC, elucidate its regulatory mechanisms, and provide insights for developing novel cardioprotective strategies.