Lunatin-1: A peptide derived from the venom of the Hadruroides lunatus scorpion modulates signaling pathways in HL60 tumor cells to induce cytotoxic effects

Lunatin-1 is a 13-residue cytotoxic peptide derived from the venom of the scorpion Hadruroides lunatus. This study investigated its early effects on cellular signaling in the human promyelocytic leukemia cell line HL-60 using integrated proteomics and phosphoproteomics. Lunatin-1 regulated key mediators of apoptosis, such as caspase-2 (CASP2) and MEK1 (MAP2K1), and impacted major signaling pathways such as MAPK and PI3K/AKT. Lunatin-1 induced caspase-dependent and -independent apoptotic signaling, reduced AKT1 phosphorylation, and promoted BAX activation, consistent with mitochondrial apoptosis. These findings demonstrate that Lunatin-1 disrupts pro-survival signaling and activates multiple cell death pathways, highlighting its potential as a therapeutic candidate for hematologic malignancies. Significance: This study provides a comprehensive analysis of the early molecular events triggered by Lunatin-1, a venom-derived peptide, in HL60 leukemia cells. Through integrated proteomic and phosphoproteomic approaches, we reveal that Lunatin-1 disrupts key survival pathways, notably MAPK and PI3K/AKT, and activates both caspase-dependent and -independent mechanisms of apoptosis. The peptide modulates proteins involved in DNA damage response, cell cycle regulation, and oxidative stress, offering insight into its multifaceted cytotoxic effects. These findings advance our understanding of venom-derived peptides as potential anticancer agents and underscore Lunatin-1's therapeutic promise for targeting resistant cancer cell populations.