Self-Assembling Amphiphilic Peptides Target the VDAC1-Hexokinase-II Complex to Induce Apoptosis in Cervical Carcinoma Cells

VDAC1, an outer mitochondrial membrane protein overexpressed in cancers, regulates apoptosis by interacting with antiapoptotic proteins and releasing apoptotic factors. We investigate novel multiblock cationic peptide amphiphiles targeting the VDAC1-Hexokinase-II complex in the mitochondria of cervical carcinoma cells. Amphiphilic peptide variants were designed by modifying the C-terminus of VDAC1 fragment LP1 with a cationic hydrophilic segment and the N-terminus with a hydrophobic domain, enabling self-assembly into nanofiber-like structures at elevated concentrations. In HeLa cells, these peptides triggered mitochondrial-mediated apoptosis through a decrease of the mitochondrial membrane potential, cytochrome <i>C</i> release, and caspase activation, suggesting a disrupted VDAC1-HK-II interaction. The mitochondria-targeting peptides showed notable selective cytotoxicity to cancer cells, with minimal effects on normal 3T3 cells. Our findings demonstrate that amphiphilic peptides for VDAC1-HK-II-targeting represent a promising mitochondria-focused therapeutic strategy for cervical cancer inhibition, combining structural self-assembly properties with enhanced apoptotic efficacy in malignant cells.