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

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible interstitial lung disease with a median survival of only 3–5 years. Its pathological hallmarks include recurrent injury to alveolar epithelial cells (AECs), defective repair, persistent fibroblast activation, and excessive extracellular matrix (ECM) deposition (1,2). Although pirfenidone and nintedanib slow lung function decline, neither reverses established fibrosis, suggesting that important drivers of disease progression remain insufficiently addressed (3).

The view of IPF as a disorder confined to the lung is becoming less adequate. Metabolomic and mechanistic studies have identified enhanced glycolysis, lactate accumulation, mitochondrial dysfunction, and lipid metabolic remodeling in IPF lung tissue and the circulation (4-6), accompanied by reactive oxygen species (ROS) overload and impaired antioxidant defenses (7). These observations suggest that pulmonary fibrosis is shaped not only by local microenvironmental injury but also by broader disturbances in metabolic-redox homeostasis, and that IPF may be better framed as an organ-specific manifestation of systemic metabolic stress (6,8).

In this context, endocrine fibroblast growth factor 21 (FGF21) has drawn interest beyond the conventional framework of local FGF signaling. FGF21 is a liver-derived circulating hormone that depends on the β-Klotho (KLB) coreceptor and is best known for its roles in energy metabolism, mitochondrial homeostasis, and adaptation to oxidative stress (9,10). A recent study found elevated plasma FGF21 alongside reduced pulmonary KLB expression in human IPF and showed that Fgf21 deficiency worsens bleomycin-induced fibrosis, whereas long-acting polyethylene glycol-conjugated FGF21 (PEG-FGF21) attenuates fibrosis and alveolar type II epithelial cell (AEC2) apoptosis (11). Taken together, these findings suggest that FGF21 may be more than a metabolic marker in IPF and may function as an endocrine redox-defense signal linking systemic metabolic stress to antifibrotic defense in the lung (11,12). This review therefore focuses on the systemic protective properties of FGF21, its potential to interrupt the ROS-transforming growth factor-β (TGF-β)-fibrosis amplification loop, and the unresolved questions that continue to limit its clinical translation.

Why endocrine FGFs represent a systemic defensive axis distinct from canonical FGF signaling

Most members of the canonical FGF superfamily act in a paracrine manner. FGF2, FGF7, and FGF10 bind heparan sulfate (HS) with high affinity and are therefore retained within the ECM, where they mediate local tissue repair and development. By contrast, the endocrine FGF subfamily, which includes FGF19, FGF21, and FGF23, has reduced HS affinity. This structural feature allows these ligands to escape local matrix retention, enter the circulation, and act on distant organs (9,13).

Systemic circulation, however, does not confer unrestricted signaling. Biological activity still depends on the co-expression of fibroblast growth factor receptors (FGFRs) and Klotho coreceptors in target tissues. FGF21 signals predominantly through fibroblast growth factor receptor 1c (FGFR1c) and requires KLB; FGF19 likewise depends on KLB; FGF23 requires α-Klotho (13,14). This receptor logic helps explain their distinct organ tropisms and physiological roles: FGF23 regulates mineral metabolism, FGF19 modulates bile acid synthesis, and FGF21 is more consistently associated with metabolic stress adaptation, mitochondrial homeostasis, and redox regulation (9,10,14). Endocrine FGF signaling should therefore be viewed not as passive long-range diffusion but as a hormone-like stress-adaptation system that is broadly available in the circulation yet selectively interpreted by tissues with the appropriate receptor context (13,14).

This distinction is particularly relevant in pulmonary fibrosis. IPF progression may depend not only on the strength of local profibrotic signaling, but also on whether systemic stress-defense capacity remains intact. Both FGFR1c and KLB have been detected in human and mouse lungs, indicating that the lung possesses the receptor machinery needed to respond to FGF21 (11,14). However, KLB expression is markedly reduced in IPF lungs, suggesting that remodeling of the receptor landscape may directly constrain FGF21 signaling and create a state of relative endocrine unresponsiveness (11). Among the three endocrine FGFs, current evidence links FGF21 most directly to metabolic-redox homeostasis and tissue protection, making it the most mechanistically relevant to IPF (9,10,15). FGF21 may therefore represent a plausible systemic signaling axis linking whole-body metabolic stress to antifibrotic defense in the lung.

How FGF21 interrupts the ROS-TGF-β-fibrosis amplification loop

In IPF, oxidative stress is not a secondary phenomenon but an active driver of fibrosis. Excess ROS injures AECs, inducing apoptosis, senescence, and maladaptive stress responses, while also activating latent TGF-β, enhancing SMAD-dependent profibrotic transcription, and driving fibroblast-to-myofibroblast transition and ECM deposition (16,17). As matrix remodeling progresses and tissue stiffness increases, hypoxia, mitochondrial dysfunction, and metabolic disturbance further increase ROS production, thereby closing a self-reinforcing ROS-TGF-β-fibrosis loop (6,7,16,17). This helps explain why blocking a single downstream effector rarely changes the course of disease. A more effective strategy may be to weaken the upstream stress conditions that maintain the loop. In this context, FGF21 is relevant not simply because of its antioxidant effects, but because it may act on two critical components of the loop at the same time: redox control and epithelial cell fate (11,18). These actions can be viewed as two complementary brakes on the ROS-TGF-β-fibrosis amplification loop, operating through redox buffering and preservation of epithelial resilience, as summarized in Figure 1.

Figure 1 Proposed model of FGF21 as an endocrine redox-defense signal in idiopathic pulmonary fibrosis. This schematic illustrates a proposed model in which liver-derived circulating FGF21 attenuates the ROS-TGF-β-fibrosis amplification loop in IPF through FGFR1c-KLB-dependent signaling in AEC2. Two linked protective mechanisms are shown: redox buffering, involving Nrf2 activation, induction of HO-1 and NQO1, increased SOD and T-AOC, and reduced MDA; and epithelial resilience, involving inhibition of PI3K-AKT-mTOR signaling, enhanced autophagy, reduced apoptosis, and improved AEC2 survival. Reduced KLB expression in IPF lungs is indicated as a potential constraint on pulmonary responsiveness to circulating FGF21. The schematic also summarizes three key translational uncertainties: compensation versus insufficiency, receptor bottleneck, and mechanistic hierarchy. Orange arrows indicate pathological amplification; green arrows indicate protective activation; red dashed lines indicate inhibitory braking; and blue arrows indicate endocrine delivery from liver to lung. AEC2, alveolar type II epithelial cell; AKT, protein kinase B; ECM, extracellular matrix; FGF21, fibroblast growth factor 21; FGFR1c, fibroblast growth factor receptor 1c; HO-1, heme oxygenase-1; IPF, idiopathic pulmonary fibrosis; KLB, β-Klotho; MDA, malondialdehyde; mTOR, mechanistic target of rapamycin; NQO1, NAD(P)H quinone dehydrogenase 1; Nrf2, nuclear factor erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; T-AOC, total antioxidant capacity; TGF-β, transforming growth factor-β.

The first protective mechanism involves nuclear factor erythroid 2-related factor 2 (Nrf2)-associated antioxidant defense. In bleomycin models, exogenous FGF21 increases superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC), reduces malondialdehyde (MDA) and other lipid peroxidation products, and is accompanied by decreased alpha-smooth muscle actin (α-SMA) expression and collagen deposition (18,19). These findings are consistent with activation of Nrf2-associated antioxidant programs, including heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), which are implicated in protection against pulmonary fibrosis (18-20). The key point is not that FGF21 replaces other antioxidant pathways, but that it incorporates antioxidant control into a broader program of systemic stress adaptation. In doing so, it may raise the threshold for oxidative injury and dampen TGF-β activation at an upstream level.

The second protective mechanism concerns epithelial cell fate. FGF21 can inhibit the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K-AKT-mTOR) signaling, restore autophagic flux, and improve AEC2 survival under persistent injury (21). Ghanem and colleagues further showed that PEG-FGF21 significantly reduces AEC2 apoptosis in bleomycin-treated lungs, whereas Fgf21 deficiency aggravates AEC2 injury and fibrosis (11). This is mechanistically important because fibrosis is sustained not only by fibroblast overactivation but also by ongoing AEC2 loss and failed epithelial repair (22,23). By improving epithelial stress tolerance, FGF21 reduces a pathological input that perpetuates the amplification loop rather than merely limiting a downstream consequence.

FGF21, therefore, differs from single antioxidants or isolated anti-apoptotic interventions. It may restrain signal amplification by reducing ROS burden and attenuating TGF-β-driven transcription, which also lowers tissue damage input through improved AEC2 survival (11,18,21). Taken together, evidence from studies of Nrf2 signaling, autophagy regulation, and AEC2 apoptosis supports the view that the pulmonary protective effects of FGF21 arise from integrated control of redox state and epithelial cell fate (20-23).

These protective effects should also be considered within a broader metabolic context. IPF is accompanied by enhanced glycolysis, lactate accumulation, mitochondrial dysfunction, and lipid metabolic reprogramming, and FGF21, as a canonical metabolic stress hormone, may exert part of its pulmonary benefit by modulating this systemic metabolic background (4-6,9,10). Available data further suggest that cross-organ metabolic communication, including regulation of the FGF21 axis by host metabolic state and the gut microbiota, may shape the overall output of this pathway (24). Even so, effective signaling in the diseased lung will still depend on local receptor competence. This constraint becomes especially important when pulmonary KLB downregulation occurs and leads directly to the translational questions discussed below (11,12).

Translational potential and key unresolved issues

From a translational perspective, the case for FGF21 in pulmonary fibrosis is no longer purely hypothetical. Ghanem and colleagues reported elevated plasma FGF21 together with reduced pulmonary KLB expression in human IPF, and showed in bleomycin-treated mice that Fgf21 deficiency worsens fibrosis and AEC2 apoptosis, whereas long-acting PEG-FGF21 improves fibrotic indices and preserves AEC2 survival (11). An accompanying editorial placed these findings within the framework of endocrine FGF-mediated interorgan communication and proposed KLB as a potential biomarker for patient stratification and response prediction (12). Together, these observations support both pathobiological plausibility and early translational relevance of the FGF21 axis in IPF. The current evidence base and the major unresolved translational questions are summarized in Table 1.

At the same time, FGF21 is not yet a mature antifibrotic target, and its path to clinical translation is still limited by three major unresolved issues.

The first concerns the biological meaning of elevated circulating FGF21 in IPF. Increased plasma FGF21 could represent an effective compensatory response to metabolic and oxidative stress, but it may also reflect a response that is already insufficient (10,25). This distinction is important because it changes the translational logic. If the increase mainly reflects effective compensation, exogenous supplementation may be useful only within a limited window of defensive failure. If it instead signals insufficient compensation, the rationale for therapeutic augmentation becomes stronger.

The second issue is whether pulmonary KLB downregulation produces functionally meaningful relative endocrine unresponsiveness. In IPF lungs, reduced KLB expression suggests that even when circulating FGF21 is elevated or exogenous analogs are administered, signaling output in the diseased lung may still be limited by receptor availability (11). Relative FGF21 resistance has been discussed in other metabolic contexts (26), but in IPF, it remains unknown whether this constraint can be overcome through receptor-restoring strategies, local delivery, or coreceptor supplementation. It is also unclear whether KLB itself can serve as a biomarker for patient stratification.

The third issue is the dominant mechanism underlying the pulmonary protective effects of FGF21. Redox buffering, AEC2 survival, and systemic metabolic reprogramming are each supported by existing evidence (11,18,21), but their relative contributions and causal order remain undefined. This question has direct implications for intervention design. If redox control is primary, combining FGF21-based strategies with antioxidant therapy may be advantageous. If epithelial protection is dominant, alveolar-targeted delivery may be more relevant. If systemic metabolic reprogramming is central, FGF21 may need to be paired with broader metabolic interventions.

Experience from other fibrotic diseases provides a useful reference. The long-acting FGF21 analog pegozafermin significantly improved histological fibrosis in the phase 2b ENLIVEN trial in metabolic dysfunction-associated steatohepatitis (NASH; now termed MASH) (27), and related agents such as efruxifermin have demonstrated preliminary antifibrotic signals (28). These findings support the clinical feasibility of targeting the FGF21 axis in fibrotic disease, while also underscoring that development in IPF will require careful attention to receptor compatibility and response heterogeneity. These trials also highlight the need to consider safety and route of delivery. Because current FGF21 analog development has mainly relied on systemic administration, IPF-specific studies should examine whether local pulmonary delivery could offer advantages. Inhaled formulations could, in principle, increase lung exposure while limiting unnecessary systemic effects, but this approach would require preclinical evaluation of formulation stability, dosing, distal lung deposition, and receptor competence in KLB-low fibrotic lungs. It should also be clarified early in preclinical studies whether prolonged treatment could further intensify relative endocrine unresponsiveness in KLB-low diseased lungs (11,26). Current evidence supports FGF21 as a candidate signaling axis with substantial translational promise, but its development still requires mechanistic stratification and rigorous preclinical validation before it can be regarded as an established antifibrotic target.

Discussion

The significance of FGF21 in pulmonary fibrosis lies less in adding another protective factor than in reframing the disease itself. IPF appears to be driven not only by local failure of epithelial injury-repair balance, but also by the capacity of the organism to preserve metabolic-redox defense under sustained stress (8,11). From this perspective, the key question is not only how to inhibit local profibrotic signaling, but also under what systemic conditions the lung loses the ability to resist fibrotic remodeling. FGF21 offers a useful molecular entry point into this problem.

Its relevance is unlikely to depend on a single pathway. Instead, FGF21 appears to act across three interconnected levels: redox buffering through Nrf2-associated antioxidant defense, preservation of epithelial resilience through reduced AEC2 apoptosis and regulated autophagy, and broader metabolic adaptation through modulation of the systemic metabolic milieu. These mechanisms are better understood as complementary than competing. Together, they support the view of FGF21 as an endocrine redox-defense signal and distinguish it from conventional antifibrotic strategies that focus more narrowly on local profibrotic pathways.

Nevertheless, there are clear limitations with this framework. Whether elevated circulating FGF21 reflects effective compensation or inadequate adaptation, whether pulmonary KLB loss causes clinically meaningful relative endocrine unresponsiveness, and how the redox, epithelial, and metabolic layers are causally related all remain central questions for translation in IPF. More broadly, the main implication of FGF21 may be to shift antifibrotic research beyond the continued search for additional local inhibitory molecules toward the systemic metabolic-stress conditions that permit fibrosis to develop and persist. This does not diminish the value of local targeted strategies, but suggests that durable modification of IPF trajectory may ultimately require reshaping the systemic environment in which fibrosis is sustained.

Conclusions

FGF21 represents a promising but still incompletely defined candidate in IPF. Rather than simply adding another local antifibrotic target, current evidence suggests that the FGF21 axis may help connect systemic metabolic stress to pulmonary defense. Further mechanistic and preclinical studies are needed to determine whether this axis can move from biological plausibility to therapeutic relevance in IPF.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1079/prf

Funding: This work was supported by the Key Talent Project of the Organization Department of Gansu Provincial Party Committee (No. 2025RCXM035, to H.B.) and the Internal Fund of The First Hospital of Lanzhou University (No. ldyyyn2023-5, to H.B.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1079/coif). Both authors report institutional funding support for the present manuscript from the Key Talent Project of the Organization Department of Gansu Provincial Party Committee (No. 2025RCXM035) and the Internal Fund of The First Hospital of Lanzhou University (No. ldyyyn2023-5). H.B. also reports that these funds were awarded to H.B. and paid to the institution. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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