Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage

Nat Commun. 2024 Apr 3;15(1):2859. doi: 10.1038/s41467-024-47095-w.


Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Diabetes Mellitus, Experimental*
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism
  • Forkhead Transcription Factors* / genetics
  • Forkhead Transcription Factors* / metabolism
  • Humans
  • Karyopherins / metabolism
  • Mice
  • Zebrafish / metabolism


  • Forkhead Transcription Factors
  • Forkhead Box Protein O1
  • Karyopherins
  • FOXO1 protein, human