In conclusion, based on the constellation of findings presented, including the potent effects of palbociclib and auranofin against mesothelioma cell proliferation, colony formation, and the cell cycle, as well as the effect on Cyclin/CDK and pro-apoptotic/anti-apoptotic protein expression, we propose a potential model for how mitochondrial antioxidant defense and CDK4/6 may interact. Here, CDK4 is linked to mesothelioma.