biostudies-literaturePan ZNational Natural Science Foundation of China (National Science Foundation of China)31https://www.ebi.ac.uk/biostudies/studies/S-EPMC12371041biostudies-literatureUnknown14(1)Antipsychotic drugs have been shown to suppress tumor growth and induce cell death, but their clinical application remains limited. Pimozide, an FDA-approved antipsychotic, holds significant potential for cancer treatment. However, the mechanisms underlying tumor cell responses to Pimozide remain unclear. In this study, we identify a critical role for peroxisomes in mediating tumor cell resistance to Pimozide. Our findings demonstrate that Pimozide increases peroxisome numbers and that peroxisomal deficiency significantly enhances Pimozide-induced cell death. We show that peroxisomes mitigate Pimozide-induced apoptosis primarily through fatty acid oxidation and ether lipid synthesis, rather than reactive oxygen species (ROS) metabolism. Moreover, Pimozide treatment upregulates peroxisomal OncogenesisPeroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis.PMC123710413217073632370776Pan ZYang ZGuo JLi FYu FCui FYou WfalsePeroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis.Antipsychotic drugs have been shown to suppress tumor growth and induce cell death, but their clinical application remains limited. Pimozide, an FDA-approved antipsychotic, holds significant potential for cancer treatment. However, the mechanisms underlying tumor cell responses to Pimozide remain unclear. In this study, we identify a critical role for peroxisomes in mediating tumor cell resistance to Pimozide. Our findings demonstrate that Pimozide increases peroxisome numbers and that peroxisomal deficiency significantly enhances Pimozide-induced cell death. We show that peroxisomes mitigate Pimozide-induced apoptosis primarily through fatty acid oxidation and ether lipid synthesis, rather than reactive oxygen species (ROS) metabolism. Moreover, Pimozide treatment upregulates peroxisomal 2025-01-01T00:00:00Z2025 Aug2026-05-09T10:47:29.708Z2026-04-08T00:48:10.883ZS-EPMC123710414084153410.1038/s41389-025-00575-0