Aripiprazole, but Not Olanzapine, Alters the Response to Oxidative Stress in Fao Cells by Reducing the Activation of Mitogen-Activated Protein Kinases (MAPKs) and Promoting Cell Survival

Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H₂O₂-induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H₂O₂. Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H₂O₂, contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H₂O₂, whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O₂^•-, a known desensitizing factor. The physiological relevance of O₂^•- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H₂O₂, possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies.