2026-06-19 ミュンヘン大学（LMU）
＜関連情報＞
- https://www.lmu.de/en/newsroom/news-overview/news/protective-effects-of-a-metabolic-hormone-62936ce0.html
- https://www.sciencedirect.com/science/article/pii/S1550413126002214
FGF21は、硫化物シグナル伝達の増加を介して、折り畳まれていないタンパク質および統合ストレス応答を強化することにより、ERストレスを軽減する FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling
Gerald Grandl, Ann-Christine König, Fabian Metzger, Arkadiusz Liskiewicz, Tanja Hefele, Shelly Nason, Aaron Novikoff, Nada Al-Refaie, Md Abdur Rahman, Ahmed Khalil, Qian Zhang, Gustav Collden, Brian Finan, Jonathan Douros, Kirk Habegger, Alberto Cebrian-Serrano, Stefanie M. Hauck, Matthias H. Tschöp, Timo D. Müller
Cell Metabolism Available online: 16 June 2026
DOI:https://doi.org/10.1016/j.cmet.2026.05.011
Graphical abstract
Highlights
- FGF21 enhances the UPR and ISR by increasing enzymatic sulfide production
- Sulfide signals (SSs) are also induced by the UPR independently of FGF21
- FGF21 and SSs do not initiate the UPR and ISR but enhance the stress-induced response
- FGF21 action increases cellular stress resilience and reduces ER stress chronically
Summary
Fibroblast growth factor 21 (FGF21) is an endocrine hormone with broad metabolic actions at supraphysiological concentrations but unclear physiological function, related to endoplasmic reticulum (ER) stress. ER stress activates the unfolded protein response (UPR), a cellular repair mechanism that maintains cellular homeostasis during protein folding stress. Using proximity labeling, we assessed the intracellular action of FGF21 at its receptor β-klotho (KLB) and discovered associations with protein folding in the ER, ER stress, and H2S production. We found that FGF21 increases enzymatic sulfide production and enhances, but does not initiate, the UPR. This FGF21 action is blunted by genetic or pharmacological inhibition of sulfide signaling and is phenocopied by an H2S donor in vivo. FGF21 modulating the UPR requires KLB, and even physiological levels of FGF21 modulate the UPR via increased hepatic H2S production. Collectively, we reveal a novel physiological role of FGF21 as an endocrine stress hormone that enhances the UPR via increased sulfide signaling.
