• Acrolein exposure induces cardiac remodeling and dysfunction, characterized by fibrosis, impaired echocardiographic parameters, and compromised cardiomyocyte contractility and Ca2+ handling.
• Mechanistically, acrolein triggers cuproptosis, evidenced by upregulation of SLC31A1, DLAT, and FDX1, and downregulation of Fe-S cluster proteins, alongside mitochondrial damage and oxidative stress.
• The copper-sensing transcription factor MTF2, but not MTF1, is upregulated by acrolein, and molecular docking predicts direct binding of acrolein to MTF2's DNA-binding domain.
• Pharmacological inhibition of cuproptosis (TTM), mitochondrial oxidative stress (mitoTEMPO), or MTF2 (actinomycin D) alleviates acrolein-induced cardiomyocyte dysfunction, suggesting MTF2-mediated cuproptosis as a therapeutic target.
• This study provides novel insights into the cardiotoxicity of acrolein, a pervasive environmental pollutant, and highlights potential interventions for acrolein-related cardiac diseases.