FGF21 in idiopathic pulmonary fibrosis: mechanistic insights, translational potential, and unresolved questions

Idiopathic pulmonary fibrosis (IPF) remains a progressive and irreversible interstitial lung disease in which currently available antifibrotic therapies slow lung function decline but rarely alter the overall disease course. Increasing evidence suggests that IPF progression is driven not only by local epithelial injury and aberrant repair, but also by broader disturbances in systemic metabolism and redox homeostasis. Within this framework, fibroblast growth factor 21 (FGF21), a liver-derived endocrine hormone that signals through fibroblast growth factor receptors (FGFRs) in the presence of the β-Klotho (KLB) coreceptor, has emerged as a potentially relevant mediator. Recent studies have reported elevated circulating FGF21 together with reduced pulmonary KLB expression in patients with IPF, more severe bleomycin-induced fibrosis in Fgf21-deficient mice, and attenuation of fibrotic injury with preservation of alveolar type II epithelial cell (AEC2) survival after treatment with long-acting polyethylene glycol-conjugated FGF21 (PEG-FGF21). These findings suggest that FGF21 may be more than a metabolic stress marker in IPF. It may contribute to antifibrotic defense by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2)-associated antioxidant responses, preserving epithelial integrity through reduced apoptosis and regulated autophagy, and promoting broader metabolic adaptation. Several translational questions remain unresolved. These include whether elevated circulating FGF21 reflects effective compensation or inadequate adaptation, whether reduced pulmonary KLB causes relative endocrine unresponsiveness, and which mechanism is most relevant to therapeutic translation. Overall, FGF21 represents a promising but still incompletely defined mechanistic and translational candidate in IPF.