<p>Zinc homeostasis plays a critical role in cellular function, yet its dysregulation may lead to cytotoxicity. Based on the unexpected finding that excessive zinc downregulates the transcription of cardiac-related factors in mouse cardiomyocytes, this study reveals a mechanistic pathway wherein cytoplasmic zinc overload reduces histone acetyltransferase activity, subsequently lowering histone acetylation and ultimately decreasing the transcriptional levels of target genes. The universality of this mechanism was further confirmed across multiple cell types. By investigating the phenomenon of zinc-induced autophagy regulated by acetylation, we explored the potential therapeutic implications of zinc as a drug. Through comparative analysis of cells with varying sensitivity to zinc, we identified aberrant expression of zinc transporters under physiological conditions as a primary factor contributing to zinc-induced toxicity. This finding suggests that zinc transporters may serve as potential therapeutic targets. This study is the first to elucidate the molecular link between zinc homeostasis and histone acetylation, providing a novel perspective for understanding zinc metabolism-related diseases and zinc-targeted therapies.</p>