This study investigated the physiological role of FGF21 in endoplasmic reticulum (ER) stress responses, specifically whether FGF21 modulates the unfolded protein response (UPR) and integrated stress response (ISR) via sulfide (H₂S) signaling through its receptor β-klotho (KLB).
FGF21 increases enzymatic H₂S production, which enhances (but does not initiate) the UPR and ISR; this effect requires KLB, is blunted by genetic or pharmacological inhibition of sulfide signaling, and is recapitulated by an H₂S donor in vivo — even at physiological FGF21 levels.
The study is largely mechanistic and preclinical; translation to human physiology is not yet established. The precise downstream molecular targets linking H₂S to UPR enhancement are not fully defined. Supraphysiological versus physiological FGF21 concentration effects may overlap in some experimental contexts.
FGF21 acts as an endocrine stress hormone that fine-tunes ER protein-folding stress responses through H₂S signaling — a novel mechanism relevant to future therapeutic targeting of metabolic and ER stress-related diseases. Clinicians should note this pathway is preclinical; direct patient management implications are not yet established.
