Abstract / Summary
Abstract Cantharidin (CTD), a potent anticancer terpenoid, is clinically limited by its hepatotoxicity and nephrotoxicity, while its impact on the hematopoietic system-particularly on red blood cells (RBCs), remains poorly understood. This study aimed to explore CTD-induced structural and functional changes in RBCs. A series of assays were conducted, including assessments of hemolysis rate, morphological changes, programmed cell death, intracellular reactive oxygen species (ROS), lactate dehydrogenase (LDH) activity, as well as untargeted metabolomics (LC–MS) and proteomics (LC–MS/MS) analyses. Results showed that high-dose CTD (0.8 mM) caused obvious RBCs morphological abnormalities, reduced adhesion and increased intracellular ROS, leading to RBC rupture, LDH release, and ultimately triggering programmed cell death. Multi-omics profiling identified 377 differential metabolites (enriched in ABC transporters and purine metabolism) and 45 differential proteins associated with Hippo and PI3K-Akt pathways. Among these, the PI3K-Akt pathway emerged as the core mechanism underlying CTD-induced RBCs injury. Collectively, this study has accumulated data on CTD-induced morphological and functional disruptions in RBCs, providing some insights for the subsequent evaluation of toxic drugs in the hematopoietic system.