Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide, and systemic therapies such as multikinase inhibitors and anthracyclines are central to the management of advanced disease. However, treatment-related cardiovascular toxicity has emerged as a major barrier to long-term benefit, highlighting the growing relevance of cardio-oncology in HCC. This review summarizes current knowledge on the mechanisms underlying HCC therapy-associated cardiotoxicity, focusing on ferroptosis, endoplasmic reticulum stress, mitochondrial dysfunction, and endothelial injury. Sorafenib-induced cardiotoxicity involves KLF11-mediated suppression of FSP1-dependent ferroptosis defenses, dysregulation of the ATF4-SLC7A11 axis, and PTX3-driven ERK/JNK signaling, whereas doxorubicin causes dose-limiting cardiomyopathy via oxidative stress, iron overload, and inflammatory pathways. We further discuss emerging mitigation strategies, including ferroptosis inhibitors, iron chelators, ion channel modulation, and rational drug combinations that enhance antitumor efficacy while attenuating myocardial damage. Special emphasis is placed on nanotechnology-based delivery systems—such as ligand-targeted, stimuli-responsive, and prodrug-based nanoparticles—which increase intratumoral drug deposition, prolong circulation time, and markedly reduce off-target, particularly cardiac, toxicity. Finally, we highlight the potential of biomarkers such as PTX3 and ATF4 for early cardiotoxicity monitoring and risk stratification, and outline key priorities for translational research and clinical validation.
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