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Scope: Despite their essentiality, several studies have shown that either manganese (Mn) or zinc (Zn) overexposure may lead to detrimental health effects. Although Mn is transported by some of the SLC family transporters that translocate Zn, the role of Zn in hepatocellular Mn transport and Mn-induced toxicity have yet to be fully characterized. Methods and Results: The human hepatoma cell line, HepG2, is utilized. Total cellular Mn and Zn amounts are determined after cells are treated with Zn 2 or 24 h prior to Mn incubation for additional 24 h with inductively coupled plasma-based spectrometry and labile Zn is assessed with the fluorescent probe FluoZin-3. Furthermore, mRNA expression of genes involved in metal homeostasis, and mechanistic endpoints associated with Mn-induced cytotoxicity are addressed. These results suggest that Zn protects against Mn-induced cytotoxicity and impacts Mn bioavailability to a great extent when cells are preincubated with higher Zn concentrations for longer duration as characterized by decreased activation of caspase-3 as well as lactate dehydrogenase (LDH) release. Conclusions: Zn protects against Mn-induced cytotoxicity in HepG2 cells possibly due to decreased Mn bioavailability. Additionally, mRNA expression of metal homeostasis-related genes indicates possible underlying pathways that should to be addressed in future studies.