PuSH - Publication Server of Helmholtz Zentrum München: FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

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Grandl, G. ; König, A.-C. ; Metzger, F. ; Liskiewicz, A. ; Hefele, T. ; Nason, S.* ; Novikoff, A. ; Al-Refaie, N. ; Rahman, M.A. ; Khalil, A. ; Zhang, Q. ; Collden, G. ; Finan, B.* ; Douros, J.* ; Habegger, K.* ; Cebrian Serrano, A. ; Hauck, S.M. ; Tschöp, M.H. ; Müller, T.D.

FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

Cell Metab. 38, DOI: 10.1016/j.cmet.2026.05.011 (2026)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Er Stress ; Fgf21 ; H2s ; Integrated Stress Response ; Isr, β-klotho, Klb ; Sulfide Signaling ; Unfolded Protein Response ; Upr

ISSN (print) / ISBN 1550-4131

e-ISSN 1932-7420

Journal Cell Metabolism

Quellenangaben Volume: 38

Publisher Elsevier

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)
CF Metabolomics & Proteomics (CF-MPC)