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

Molecular docking across three human KEAP1 Kelch-domain crystal structures predicts squalene can fit a canonical hydrophobic cavity, with docking scores of 7.905, 7.513, and 6.756 kcal/mol.

• Why it matters: Stress-exposed stem and progenitor cells must maintain viability and niche function, yet how squalene links stress-responsive metabolism to NRF2 regulation via KEAP1 remains unclear.
• What they did: The study docked squalene to KEAP1 using structures with PDB IDs 6TYM, 6SP4, and 5CGJ, validating the protocol by native-ligand redocking (RMSD 0.826, 0.277, 0.303 Å).
• The result: Predicted binding is mainly hydrophobic and involves residues including Arg415, Arg380, and Asn414 without conventional hydrogen bonds, enabling a testable hypothesis for KEAP1–NRF2 pathway engagement.

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