Squalene as a Candidate Signalling Molecule: Computational Evidence for a Predicted KEAP1 Interaction and Implications for Stress-Induced Altruistic Stem-Cell Niche Protection

Abstract

Stem and progenitor cells exposed to cytotoxic stress must preserve both their own viability and the functional integrity of their surrounding niche. Previous investigations from our laboratory have described stress-adapted altruistic stem-cell phenotypes and demonstrated the cytoprotective potential of squalene in normal haematopoietic and mesenchymal progenitor cells through preservation of glutathione homeostasis. More recent studies have associated hypoxia-driven changes in squalene metabolism with intracellular squalene accumulation and protection against lipid peroxidation, while independent experimental evidence has implicated NRF2 in squalene-mediated cytoprotection. However, the molecular basis through which squalene may engage the NRF2 regulatory pathway remains incompletely understood. Here, we investigated the structural feasibility of a potential interaction between squalene and the KEAP1 Kelch domain using molecular docking across three human KEAP1 crystal structures (PDB IDs: 6TYM, 6SP4 and 5CGJ). The docking protocol was evaluated through native-ligand redocking, yielding RMSD values of 0.826, 0.277 and 0.303 A, respectively. Squalene was consistently accommodated within the canonical hydrophobic cavity, with predicted docking scores of 7.905, 7.513 and 6.756 kcal/mol. The predicted interaction environment was predominantly hydrophobic and involved residues including Arg415, Arg380 and Asn414, without conventional hydrogen-bond formation. These findings support the structural feasibility of squalene accommodation within the KEAP1 Kelch domain and provide a testable hypothesis connecting stress-responsive squalene metabolism with potential KEAP1 NRF2 regulation. However, docking alone does not establish direct binding, physiological accessibility, KEAP1 inhibition or functional NRF2 activation. Further biophysical, molecular-dynamics and cellular investigations are required to establish the biological significance of the predicted interaction.