Computational investigation of the interplay between cellular stress and ferroptosis in triple-negative breast cancer

Recent studies have shown that ferroptosis and cellular stress are related to triple-negative breast cancer (TNBC). This study used molecular dynamics simulations (MDS) and protein-peptide docking to pinpoint the glutathione peroxidase 4 (GPX4) protein and glucose-regulated protein 78 (GRP78) interaction site. The cyclic peptide Pep42 had previously been identified as a selective target for GRP78 on cancer cell membranes. Sequence alignments reveal that the GPX4 cyclic regions: R1 (C7-C16), R2 (C16-C29), R3 (C7-C29), and R7 (C93-C102) share sequence identity of 30.00 %, 30.77 %, 38.46 %, and 42.86 % against Pep42 peptide, respectively. Moreover, these four GPX4 regions have a grand average hydrophobicity index (GRAVY) of 1.2, 1.3, 1.2, and 1.5, respectively, similar to Pep42's GRAVY of 1.1. Additionally, they show strong binding affinities for GRP78 substrate binding domain β (SBDβ) (-6.81, -7.85, -8.77, and -7.25 kcal/mol, for R1, R2, R3, and R7, respectively). This study attempts to predict the binding site which needs further extensive experimental validation aimed at exploring potential disruptors of the GRP78 -GPX4 association. This would block ferroptosis resistance and chemoresistance in TNBC.