A nature-inspired HIF stabilizer derived from a highland-adaptation insertion of plateau pika Epas1 protein

Hypoxia-inducible factors (HIFs) play pivotal roles in numerous diseases and high-altitude adaptation, and HIF stabilizers have emerged as valuable therapeutic tools. In our prior investigation, we identified a highland-adaptation 24-amino-acid insertion within the Epas1 protein. This insertion enhances the protein stability of Epas1, and mice engineered with this insertion display enhanced resilience to hypoxic conditions. In the current study, we delved into the biochemical mechanisms underlying the protein-stabilizing effects of this insertion. Our findings unveiled that the last 11 amino acids within this insertion adopt a helical conformation and interact with the α-domain of the von Hippel-Lindau tumor suppressor protein (pVHL), thereby disrupting the Eloc-pVHL interaction and impeding the ubiquitination of Epas1. Utilizing a synthesized peptide, E14–24, we demonstrated its favorable membrane permeability and ability to stabilize endogenous HIF-α proteins, inducing the expression of hypoxia-responsive element (HRE) genes. Furthermore, the administration of E14–24 to mice subjected to hypoxic conditions mitigated body weight loss, suggesting its potential to enhance hypoxia adaptation.