Antifibrotic Strategies Targeting Phosphodiesterase-4 in Idiopathic Pulmonary Fibrosis: Molecular Mechanisms and Clinical Translation

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease characterised by progressive scarring of the lung parenchyma, with its pathology marked by irreversible structural destruction and functional decline caused by abnormal extracellular matrix (ECM) deposition.¹ Epidemiological surveys have shown a rising global incidence of IPF worldwide,² while the median survival following diagnosis remains less than five years, underscoring its poor prognosis.³ Current evidence supports a polygenic-environmental interaction model, in which long-term environmental exposures (tobacco smoke, occupational dust) and genetic susceptibility act synergistically to drive disease initiation and progression.⁴

The pathogenic cascade is often described as being initiated by repeated microinjury to alveolar epithelial cells (AECs), leading to disruption of the balance between the endoplasmic reticulum stress response and mitochondrial homeostasis, and ultimately to failure of epithelial repair programmes.⁵ However, it is increasingly recognised that fibrotic remodelling reflects complex interactions among epithelial cells, immune cells, mesenchymal cells, and the extracellular matrix, rather than a single linear pathway.⁶ Damaged epithelial cells release pro-inflammatory cytokines such as IL-6 and TNF-α, which activate alveolar macrophages to secrete pro-fibrotic mediators including TGF-β and PDGF. These factors, in turn, promote fibroblast activation and the accumulation of myofibroblasts (MyoFBs), thereby establishing a self-perpetuating inflammation-fibrosis cycle.⁷ MyoFBs can arise from multiple cellular sources, including resident fibroblasts and other mesenchymal precursor populations.⁸

Molecular pathology studies have further revealed a networked interaction of multidimensional molecular events, including redox imbalance (abnormal accumulation of reactive oxygen species), cell cycle arrest via p16/p21 activation, impaired autophagy, and epithelial–mesenchymal transition (EMT). These events collectively mediate irreversible lung structural remodelling.^9,10 Clinically, IPF typically manifests with progressive exertional dyspnoea, non-expectorative cough and generalised fatigue, which together cause substantial declines in quality of life (QOL). Notably, more than 60% of patients with IPF have at least one comorbidity, including pulmonary hypertension, ischaemic heart disease and pulmonary malignancy.¹¹

Despite advances in clinical management, significant therapeutic challenges remain. The current standard of care relies primarily on two antifibrotic agents, nintedanib and pirfenidone, together with supportive interventions such as oxygen therapy and pulmonary rehabilitation.¹² Both nintedanib, a multi-receptor tyrosine kinase inhibitor,¹³ and pirfenidone, which acts through multiple antifibrotic mechanisms,¹⁴ have been shown to slow disease progression, reducing the annual decline in lung function by approximately 50%. However, neither drug reverses established fibrosis or restores lung architecture, and both are limited by adverse events (such as liver function abnormalities and phototoxic reactions) as well as inadequate efficacy in addressing comorbidities.¹⁵ This therapeutic dilemma highlights the urgent need to develop novel therapeutic paradigms.

In recent years, intervention strategies targeting the phosphodiesterase 4 (PDE4) signalling pathway have attracted considerable research interest.¹⁶ As a key enzyme regulating the metabolism of the second messenger cyclic adenosine monophosphate (cAMP), PDE4 contributes to fibrosis by modulating immune cell activation and matrix remodelling. PDE4 is one of several phosphodiesterase isoforms involved in cAMP regulation.¹⁷ PDE4 inhibitors act by increasing intracellular cAMP levels, thereby suppressing inflammatory mediator release, inhibiting TGF-β signalling and modulating fibroblast differentiation phenotypes.¹⁸ Notably, this class of drugs has demonstrated dual anti-inflammatory and anti-fibrotic efficacy in fibrosis-related disease models such as systemic sclerosis and chronic obstructive pulmonary disease. However, their long-term benefit-risk profile in the treatment of IPF require validation through large-scale multicentre clinical trials.

Pathogenesis of IPF

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by complex interactions among genetic susceptibility, environmental exposures, and dysregulated tissue repair responses.¹⁹ Rather than a single linear pathway, IPF is increasingly conceptualised as a self-perpetuating cycle in which repetitive epithelial injury and impaired regeneration promote persistent inflammatory signalling, fibroblast activation, and pathological extracellular matrix (ECM) remodelling. In this context, immune dysregulation contributes to disease initiation and persistence, particularly through macrophage–fibroblast crosstalk and cytokine-mediated amplification loops that sustain profibrotic signalling.^20–22 Although this section focuses on IPF, many of the mechanisms summarised below are shared across lung fibrosis more broadly and are commonly examined using experimental fibrosis models; IPF is discussed specifically where human disease evidence and clinical outcomes are available.

Imbalance of Immune Homeostasis

IPF has historically been described as an “atypical inflammatory fibrotic disease” dominated by myofibroblast proliferation and ECM deposition; however, accumulating evidence indicates that immune microenvironment disturbances contribute to both disease onset and progression.²⁰ IPF lung tissues have been reported to exhibit persistent activation of alveolar macrophages with enhanced production of profibrotic mediators, altered T-cell homeostasis including disruption of the Th17/Treg balance, and aberrant B-cell activation with increased autoantibody positivity.²¹ These immune perturbations may reinforce fibrosis through cell–cell interactions, such as macrophage–fibroblast signalling, and cytokine-driven feedback loops involving mediators including IL-13 and CCL18.^21,22 Single-cell approaches further support immune cell state remodelling during IPF progression, including expansion of macrophage populations with profibrotic transcriptional signatures and changes in T-cell functional states.²²

Macrophage-Centred Profibrotic Signalling

Macrophages play a central role in linking inflammatory injury to progressive fibrosis and represent a key immune node in IPF pathobiology.²³ Early inflammatory macrophage activation has been associated with epithelial barrier disruption and increased production of pro-inflammatory mediators, including TNF-α, IL-1β, and IL-6, whereas later profibrotic macrophage states are characterised by elevated secretion of mediators such as TGF-β and PDGF that promote fibroblast activation and ECM synthesis.^22,23 Single-cell transcriptomic studies have described profibrotic macrophage subsets and lipid-associated metabolic signatures in IPF lungs, suggesting that immunometabolic adaptations may contribute to persistent matrix remodelling.²² In addition, macrophage-derived extracellular vesicles have been reported to participate in epithelial–mesenchymal signalling and fibroblast activation in experimental systems.²⁴

Other Innate and Adaptive Immune Contributors

Beyond macrophages, additional immune cell populations have been implicated in shaping the profibrotic microenvironment. Neutrophil-associated processes, including the formation of neutrophil extracellular traps, have been reported in bronchoalveolar lavage fluid and linked to epithelial injury and fibroblast activation in experimental studies.^25–28 Mast cells, T-cell subset imbalance involving Th17/Treg dysregulation, and aberrant B-cell activation with tertiary lymphoid structure formation and autoantibody production have also been described in IPF, with proposed roles in sustaining cytokine signalling and fibroblast responses.^19,29–38 γδ T cells have additionally been reported to contribute through cytokine secretion and interactions within broader immune networks in fibrotic lung tissue.^39–42

Immunometabolic Reprogramming

In parallel with immune cell dysregulation, the IPF microenvironment exhibits metabolic remodelling that may amplify inflammatory and mesenchymal signalling. Reported alterations include increased glycolytic flux, altered glutamine utilisation, and enhanced fatty-acid oxidation pathways that influence macrophage activation states and fibroblast contractility. Preclinical studies targeting selected metabolic nodes have shown attenuation of fibrotic endpoints, supporting immunometabolic reprogramming as a contributor to disease progression.^30,43 (Figure 1).

Figure 1 Immune mechanisms contributing to IPF pathogenesis. Schematic overview of immune cell populations implicated in idiopathic pulmonary fibrosis, including alveolar macrophages, T-cell subsets, and mast cells. These cells contribute to a profibrotic microenvironment through cytokine and mediator release, promoting fibroblast activation, myofibroblast differentiation, and extracellular matrix deposition. The cyclic adenosine monophosphate (cAMP)–phosphodiesterase 4 (PDE4) axis is depicted as a modulatory signalling node influencing immune activation states and downstream fibrotic responses. Solid arrows indicate established pathways, whereas dashed arrows denote hypothesised or emerging links.

Collectively, these immune and immunometabolic disturbances contribute to a profibrotic ecosystem characterised by persistent cytokine signalling, altered intercellular communication, and fibroblast activation. Importantly, many of these pathways converge on intracellular second-messenger systems, particularly cyclic adenosine monophosphate (cAMP), which regulates inflammatory mediator release, immune cell activation states, and fibroblast behaviour.⁴⁴ Given that phosphodiesterases control cAMP degradation, dysregulated phosphodiesterase activity may represent a mechanistically relevant link between immune microenvironment alterations and progressive fibrotic remodelling, providing a rationale for targeting the PDE4 signalling pathway in IPF.⁴⁵

Dysregulation of Tissue Repair Mechanisms

The progression of IPF is closely associated with abnormalities in tissue repair and regenerative responses, in which persistent injury signals, maladaptive innate immune activation, and impaired regeneration may reinforce a self-sustaining cycle of fibrosis. Clinical cohort studies have reported that the pulmonary microenvironment in IPF is characterised by ongoing low-grade inflammatory activity, including increased NET-related deposits, evidence of prolonged NLRP3 inflammasome activation, and elevated IL-1β/IL-18 levels.⁴⁶

Epithelial Regeneration Disorders

Defective alveolar epithelial regeneration is considered a key contributor to IPF pathobiology. Dysregulation of the Wnt/β-catenin pathway has been associated with impaired AT2 cell proliferative capacity through mechanisms involving altered transcriptional regulation, including aberrant TCF4 activity and reduced Axin2 expression. In experimental organoid systems, treatment with the β-catenin/CBP interaction inhibitor ICG-001 has been reported to improve epithelial regenerative responses.⁴⁰ Senescent alveolar epithelial cells, reported to be increased in IPF compared with controls, may contribute to fibroblast activation by releasing SASP mediators (eg, IL-6, MMP3, PAI-1) and by altering immune cell activation states, thereby sustaining profibrotic signalling.⁴⁷ Single-cell metabolomics studies have further suggested that impaired mitochondrial quality control in senescent epithelial cells may contribute to altered energy homeostasis through pathways involving AMPK and mTORC1 signalling.⁴⁷

Abnormal Fibroblast Activation

Fibroblast activation and expansion of α-smooth muscle actin-positive myofibroblasts are hallmarks of IPF progression. Aberrant mechanosensing and sustained activation of integrin-linked signalling, including β1-associated pathways and YAP activity, have been implicated in maintaining myofibroblast phenotypes in experimental settings.⁴⁸ Activated fibroblasts have also been reported to exhibit metabolic reprogramming, including increased glycolytic flux (with upregulated HK2 and LDHA) and enhanced glutamine utilisation, with mTORC1-4EBP1 signalling proposed as a maintenance axis.⁴⁹ In intervention studies, the GLS1 inhibitor CB-839 has been reported to attenuate collagen-related endpoints, with proposed mechanisms involving altered α-ketoglutarate availability and downstream epigenetic regulation. Spatial transcriptomic observations have further described co-localisation of profibrotic signalling with ECM stiffness gradients within fibrotic lesions, supporting a model in which biochemical and biomechanical cues jointly reinforce fibroblast activation.

Together, inflammatory mediators and dysregulated repair responses intersect with intracellular signalling nodes that are regulated by cyclic adenosine monophosphate (cAMP), which can influence immune activation states, senescence-associated signalling, and fibroblast effector functions.⁵⁰ As PDE4 is a major regulator of cAMP degradation in inflammatory and structural cells, targeting PDE4 provides a mechanistically plausible strategy to modulate interconnected profibrotic pathways relevant to IPF.

Disruption of Microenvironmental Homeostasis

Microenvironmental dysregulation in IPF involves both altered biomechanical properties of the lung parenchyma and remodelling of intercellular signalling networks.⁵¹ Excess ECM accumulation can enhance mechanotransduction pathways in epithelial and mesenchymal compartments, including integrin-FAK-associated signalling and YAP/TAZ activation, which may further reinforce profibrotic programmes. Single-cell intercellular analyses have reported aberrant epithelial–fibroblast signalling circuits in IPF tissues, including interactions involving IL-11-expressing epithelial populations and PDGFRα⁺ fibroblasts, with miR-21-5p implicated as a candidate mediator in some models. These interactions have been proposed to contribute to LOXL2-associated collagen cross-linking and sustained TGF-β/Smad3 signalling.⁵² Spatial metabolomics studies have also reported altered glutamine–glutamate patterns within fibrotic lesions, with mTORC1-4EBP1 signalling suggested as a potential axis supporting metabolic adaptation in the fibrotic microenvironment (Figure 2).

Figure 2 Dysregulation of inflammatory signalling pathways in IPF. Key profibrotic and inflammatory signalling pathways implicated in IPF, including TGF-β/Smad, MAPK/p38, JAK–STAT, and NLRP3/NF-κB cascades. Activation of these pathways promotes fibroblast activation, extracellular matrix accumulation, and sustained inflammatory signalling. cAMP–PDE4 signalling is shown as an upstream modulatory mechanism that indirectly influences pathway intensity through PKA-CREB and EPAC-dependent processes. Solid arrows represent established signalling events, and dashed arrows represent proposed or context-dependent mechanisms.

Key Signalling Axes in IPF

TGF-β signalling is widely regarded as a central regulatory pathway in pulmonary fibrosis.⁵³ Canonical Smad signalling, including TβRII-dependent phosphorylation of Smad2/3, promotes fibroblast-to-myofibroblast differentiation and ECM gene expression, while non-canonical pathways such as MAPK/p38 and PI3K/AKT/mTOR signalling have been implicated in profibrotic transcriptional and metabolic regulation. Microregional or compartmentalised activation of TGF-β signalling has been reported in progressive fibrotic lung tissues, and cross-talk with Wnt/β-catenin and Notch signalling has been proposed to contribute to the persistence of profibrotic microenvironments.⁵⁴

Innate immune signalling pathways also contribute to inflammatory amplification and epithelial injury in IPF. The NLRP3 inflammasome–IL-1β axis has been reported to promote maturation of IL-1β through ASC/caspase-1/NLRP3 complex activation, with downstream IL-1R/MyD88 signalling linked to NF-κB pathway activation and pyroptosis-related processes in experimental contexts. In clinical analyses, activation markers of this pathway have been reported to correlate with lung function decline in IPF cohorts.²²

The JAK–STAT system, particularly sustained STAT3 activation, has been implicated in fibrosis through transcriptional regulation of profibrotic mediators, modulation of immune regulatory programmes, and interactions with cellular metabolism. STAT3 activity has been linked to increased expression of TGF-β1-associated programmes, epigenetic regulation involving HDAC3-dependent effects on FoxO1 accessibility, and metabolic shifts that may enhance glutamine utilisation in fibroblasts.⁵⁵ Preclinical studies have reported that selective JAK1 inhibition can reduce IL-6 levels in bronchoalveolar lavage fluid, supporting continued evaluation of pathway-targeted strategies (Figure 3).

Figure 3 Dysregulation of tissue repair and microenvironmental homeostasis in IPF. Mechanisms underlying defective epithelial regeneration, aberrant fibroblast activation, and extracellular matrix stiffening in IPF. Alterations in Wnt/β-catenin signalling, integrin-mediated mechanotransduction, and YAP/TAZ activation contribute to impaired tissue repair and progressive fibrosis. Established pathways are distinguished from proposed or emerging mechanisms, highlighting the convergence of biomechanical and biochemical signals in sustaining the fibrotic microenvironment.

Phosphodiesterase 4 Regulates IPF Pathogenesis

Phosphodiesterase 4 (PDE4), a key enzyme regulating cyclic adenosine monophosphate (cAMP) signalling, is involved in IPF pathogenesis through modulation of inflammatory signalling and fibroproliferative responses.⁵⁶ PDE4 inhibition increases intracellular cAMP and activates downstream protein kinase A (PKA) signalling, which can suppress pro-inflammatory mediator release and reduce profibrotic signalling activity in relevant cellular and preclinical models.⁵⁰

At the immune regulation level, PDE4 inhibition has been reported to modulate innate and adaptive immune responses, including macrophage activation states and inflammatory cytokine production, thereby reducing the profibrotic microenvironment that sustains fibroblast activation.⁵⁷ At the tissue remodelling level, PDE4 inhibition has been associated with attenuation of fibroblast activation and extracellular matrix accumulation in experimental settings, supporting its potential as an anti-fibrotic strategy in lung fibrosis.⁵⁶

Proposed or emerging mechanisms. In addition to these core cAMP-mediated actions, PDE4 inhibition has been suggested to influence additional downstream pathways related to TGF-β signalling, epithelial injury responses, and cellular metabolism. However, several of these mechanisms remain proposed and require further validation in IPF-specific models and clinical studies.⁵⁷

Phosphodiesterase 4

The cyclic nucleotide phosphodiesterase (PDE) superfamily comprises 11 families (PDE1 to PDE11) that regulate intracellular signalling by catalysing the hydrolysis of cyclic nucleotide second messengers, principally cAMP and cGMP.⁴⁵ Members of this superfamily share a conserved catalytic core and regulatory regions that influence subcellular localisation, assembly into signalling complexes, and responsiveness to post-translational modification.⁴⁵ The biological diversity across PDE families and isoforms contributes to compartmentalised cyclic nucleotide signalling, enabling fine regulation of cell-type-specific responses.

Cyclic nucleotide signalling plays a central role in biological processes relevant to fibrotic lung disease, including inflammatory responses, epithelial repair, fibroblast activation, and metabolic regulation.⁵⁸ PDE4 isoforms are cAMP-specific hydrolases and are expressed in multiple cell populations relevant to lung inflammation and remodelling, including macrophages, T lymphocytes, fibroblasts, and epithelial cells. Pharmacological inhibition of PDE4 increases intracellular cAMP, which can activate downstream pathways such as PKA–CREB and EPAC–Rap1 signalling.⁵⁹ In experimental systems, PDE4 inhibition has been associated with suppression of inflammatory mediator expression (including TNF-α and IL-6), enhancement of epithelial barrier-associated programmes, and attenuation of profibrotic signalling linked to pathways such as TGF-β/Smad3 and Wnt/β-catenin.^59–61 PDE4 inhibition has also been reported to increase anti-inflammatory programmes, including CREB-associated regulation of IL-10 expression.^60,61 Emerging studies further suggest that PDE4 inhibitors may influence immunometabolic features of fibrotic microenvironments; however, these effects remain model-dependent and require further validation in IPF-relevant experimental systems and clinical contexts.

Phosphodiesterase 4 Inhibitors

Clinical development of PDE4 inhibitors has expanded across inflammatory and immune-mediated diseases, with efficacy demonstrated in selected Th2-driven inflammatory conditions and autoimmune disorders.⁶² In fibrosis-relevant experimental models, PDE4 inhibition has been associated with anti-inflammatory and antifibrotic effects through cAMP-dependent pathways including PKA and EPAC signalling. However, clinical development of systemic PDE4 inhibitors has been constrained by dose-limiting gastrointestinal adverse events, including nausea and vomiting, reported in dose-escalation settings. These adverse effects have been linked to PDE4 isoform distribution and central mechanisms, and have motivated efforts to optimise selectivity and delivery strategies.⁶³

Accordingly, several approaches have been explored to improve therapeutic index, including subtype-selective inhibitors with increased activity toward PDE4B, inhaled formulations designed to increase lung exposure relative to systemic exposure, and multi-target strategies combining PDE4 inhibition with additional antifibrotic mechanisms.⁶³ Candidate approaches relevant to fibrotic lung disease include inhaled PDE4 inhibitors (eg, GSK256066), dual-mechanism inhibitors (eg, PDE4 and tyrosine kinase inhibition), and subtype-selective strategies aimed at improving tolerability while maintaining biological activity (Figure 4).⁶³

Figure 4 Mechanistic framework of PDE4 inhibition in fibrotic lung disease. Proposed mechanisms by which PDE4 inhibition modulates inflammatory and fibrotic processes in the lung. Inhibition of PDE4 increases intracellular cAMP levels, activating PKA and EPAC signalling to suppress inflammatory mediator production, attenuate fibroblast activation, and modulate profibrotic TGF-β/Smad signalling. Potential metabolic and mitochondrial effects are depicted as emerging mechanisms. Subtype-selective inhibition of PDE4B, relative to PDE4D, is illustrated to reflect efforts to optimise therapeutic efficacy while limiting central nervous system–related adverse effects. Solid arrows denote established effects, and dashed arrows indicate proposed mechanisms.

Nerandomilast

Nerandomilast (BI 1015550) is a PDE4 inhibitor with preference for PDE4B and has been developed for fibrotic lung diseases including IPF and progressive pulmonary fibrosis (PPF).⁶⁴ Its proposed therapeutic rationale is based on PDE4B-biased inhibition leading to increased intracellular cAMP signalling and downstream modulation of inflammatory and fibrotic pathways relevant to lung fibrosis.⁶⁴ Nerandomilast has progressed through late-stage clinical development programmes.

Across clinical studies, nerandomilast has been associated with gastrointestinal adverse events, including nausea, diarrhoea, and related symptoms, consistent with known class effects of PDE4 inhibition. Interpretation of tolerability relative to other PDE4 inhibitors should be cautious in the absence of head-to-head trials, given differences in study populations, dosing regimens, and trial design. The reduced activity of nerandomilast against PDE4D relative to PDE4B has been proposed as a potential contributor to tolerability in relevant settings, but this hypothesis requires careful interpretation alongside clinical trial data.⁶⁴

The first-in-human evaluation (NCT04419506) used a randomised, double-blind, placebo-controlled dose-escalation design.⁶⁵ Healthy male volunteers received single ascending doses or multiple ascending doses, and an extended cohort included patients with IPF treated for 12 weeks. Treatment-emergent adverse events were reported, with headache and gastrointestinal symptoms among the most frequent events. Most events were mild to moderate, no treatment-related serious adverse events were reported, and drug exposure was higher in the IPF cohort than in healthy volunteers, suggesting potential disease-related influences on pharmacokinetics.⁶⁵

A Phase II study (NCT05321069) used a multicentre, randomised, double-blind, placebo-controlled design in patients with confirmed IPF and evaluated change in forced vital capacity (FVC) over the treatment period.⁶⁶ Results suggested differences in FVC trajectories across subgroups with and without background antifibrotic therapy. Treatment-emergent adverse events were common and predominantly gastrointestinal, and most events were mild to moderate.⁶⁶ These findings supported continued evaluation in confirmatory trials.

International multicentre Phase III trials in IPF and PPF were conducted as randomised, double-blind, placebo-controlled studies with treatment durations of at least 52 weeks and stratification by background antifibrotic therapy.⁶⁷ Across studies, nerandomilast was associated with a reduced rate of FVC decline compared with placebo over the observation period, including among participants receiving background antifibrotic therapy.⁶⁷ Overall adverse event rates were broadly comparable across groups, while discontinuations due to adverse events showed dose-related patterns. Gastrointestinal events, particularly diarrhoea, were among the leading reasons for discontinuation.⁶⁷ Collectively, these findings support continued evaluation of nerandomilast as a therapeutic option in fibrotic lung disease, while highlighting tolerability considerations relevant to PDE4 inhibition.

Preclinical pharmacodynamic studies reported activity of BI 1015550 in bleomycin-induced and silica-induced models of pulmonary fibrosis in mice, including reductions in lung hydroxyproline and improvement in structural indices.⁶⁸ In vitro experiments have suggested attenuation of TGF-β1-induced profibrotic gene expression and modulation of fibroblast signalling, with additive effects reported alongside nintedanib in selected assays.⁶⁸ Molecular docking analyses have proposed isoform-selective binding features that may contribute to reduced inhibitory activity against PDE4D relative to PDE4B, but such structural interpretations should be considered supportive rather than definitive predictors of clinical tolerability.⁶⁸

Roflumilast

Roflumilast (Daxas®) is an oral PDE4 inhibitor that can be used to reduce the risk of acute exacerbations of chronic obstructive pulmonary disease (COPD). Its potential relevance to fibrotic mechanisms has been explored in experimental studies. Metabolic profiling based on nuclear magnetic resonance (NMR) spectroscopy revealed significant changes in lung tissue metabolism following bleomycin-induced pulmonary fibrosis in mice. The analysis showed that amino acid metabolites, including proline and glycine, were significantly accumulated in fibrotic lungs compared with control animals, while intermediates associated with the fatty acid β-oxidation pathway were significantly reduced. These metabolic disturbances suggest that the fibrotic process is characterised by a shift from energy-producing lipid metabolism to biosynthetic processes.⁶⁹ Roflumilast intervention (1 mg/kg per day) was reported to reverse these metabolic disturbances, resulting in a reduction of proline levels, a key precursor of collagen synthesis, while elevating glutathione reductase activity to improve oxidative stress status.

In an allogeneic lung transplantation model (B10.D2→BALB/c), roflumilast inhibited the gene expression of cytokines and pro-fibrotic mediators (IL-6, IL-1β, TGF-β, CTGF) and elevated the proportion of CD4⁺ FoxP3⁺ regulatory T-cell infiltration compared to the control group.⁷⁰ In C57BL/6J mice, prophylactic administration (5 mg/kg per day) reduced lung hydroxyproline content and decreased the right ventricular hypertrophy index. Transcriptome analyses showed reduced expression of key fibrosis-related genes (COL1A1, EDN1, etc.) and a decrease in the concentration of the lipid peroxidation marker MDA.⁷¹

Recent studies have also reported that roflumilast can inhibit the formation of neutrophil extracellular traps (NETs). In neutrophils from cystic fibrosis (CF) patients, NET production was inhibited and histone H3 citrullination levels were significantly reduced.⁷² In a model of Pseudomonas aeruginosa chronic airway infection, treated mice showed decreased free DNA content in bronchoalveolar lavage fluid and increased body weight recovery compared to controls, suggesting modulation of innate immunity in an infection-associated setting. Collectively, these findings suggest that PDE4 inhibition may influence pathways linked to inflammation, oxidative stress, and fibrotic remodelling in experimental models, although clinical relevance for lung fibrosis requires further confirmation.

Mangosteen Derivatives

Huang’s research team⁷³ reported a novel class of phosphodiesterase 4 (PDE4) inhibitors based on structural modification of α-mangostin. Among these, compound 18a exhibited oral bioavailability and target selectivity in preclinical evaluation. The derivative showed a half-inhibitory concentration of 4.2 nmol/L against PDE4 isoforms, and molecular docking analysis reported differential binding characteristics compared with the clinical drug roflumilast. Toxicological evaluation reported that no adverse effects such as central vomiting were observed in the 10 mg/kg dose group administered by gavage to rats, whereas the positive control rolipram triggered gastrointestinal toxicity at an equivalent dose (1 mg/kg).⁷³

In a bleomycin-induced rat model of lung fibrosis, 18a (10 mg/kg, once daily) administered orally inhibited collagen deposition. Improvement in lung histopathological scores was reported to be statistically comparable to that of high-dose pirfenidone (150 mg/kg). The study further suggested that, by optimising physicochemical parameters such as lipophilicity and ionisation constants, this compound may reduce central nervous system side effects reported with conventional PDE4 inhibitors while maintaining PDE4 inhibitory activity.⁷³ These findings support 18a as an early preclinical candidate with translational potential, but current evidence remains limited to preclinical models, and validation in well-designed clinical studies with meaningful endpoints is required.⁷³

2-Arylbenzofurans

Wang’s research team⁷⁴ designed and synthesised a class of small molecule compounds targeting PDE4 based on a 2-arylbenzofuran backbone. The lead molecule, L13, showed nanomolar inhibitory activity against PDE4 in vitro. In a bleomycin-induced mouse model of lung fibrosis, L13 (10 mg/kg) was reported to improve lung histopathological features and reduce extracellular matrix deposition. In the same experimental setting, the antifibrotic effect was reported to be comparable to that of pirfenidone (300 mg/kg). Structure–activity relationship analyses suggested that introduction of aryl substituents to optimise molecular rigidity and hydrophobicity enhanced interaction with the PDE4 catalytic domain and improved plasma stability and oral bioavailability. The authors further reported that optimisation of physicochemical properties, including the lipid–water partition coefficient, may reduce off-target risk while maintaining enzyme inhibitory activity.⁷⁴

These findings support 2-arylbenzofuran derivatives as early preclinical PDE4-directed candidates in experimental lung fibrosis models. However, evidence remains limited to preclinical studies, and further pharmacology, safety, and clinical evaluation are needed before translational conclusions can be drawn.

Rolipram

Pharmacological studies by Wu et al⁷⁵ reported that rolipram, a prototypical PDE4 inhibitor, elevates intracellular cAMP by inhibiting PDE4-mediated cAMP hydrolysis. In experimental settings, rolipram has been used as a reference compound to demonstrate anti-inflammatory effects and to explore antifibrotic signalling pathways linked to cAMP elevation.⁷⁵

However, rolipram is not widely used clinically due to tolerability limitations, and its primary value in this context is as a mechanistic tool compound rather than a practical therapeutic option.

Aminophylline

In a study by Suat Ekin et al,⁷⁶ theophylline was evaluated in a bleomycin-induced rat model of pulmonary fibrosis. The authors reported that bleomycin exposure was associated with oxidative stress and inflammatory activation, including reduced antioxidant enzyme activity and increased malondialdehyde levels, alongside activation of NF-κB signalling and increased IL-6 expression. Theophylline treatment (75 mg/kg) was reported to restore antioxidant markers, reduce lipid peroxidation, and attenuate inflammatory signalling, with improvement in histopathological findings.⁷⁶

As a non-selective agent with multiple pharmacologic actions, theophylline and aminophylline are best interpreted as providing supportive mechanistic context rather than serving as selective PDE4-targeted antifibrotic strategies.

AA6216

Matsuhira’s group⁷⁷ used a bleomycin-induced mouse model of lung fibrosis to evaluate the regulation of segregated-nucleus-containing atypical monocytes (SatMs) by a novel compound, AA6216 (10 mg/kg per day, orally), compared with the clinical antifibrotic drug nintedanib (100 mg/kg per day, orally). The experimental design included continuous dosing from pre-treatment to day 8. Pathological analyses showed reduced accumulation of SatMs in the lung parenchyma in the AA6216-treated group, whereas SatM numbers were increased in the nintedanib-treated group under the conditions reported. In an in vitro bone marrow-derived SatM culture system, AA6216 inhibited TNF-α secretion in a concentration-dependent manner.⁷⁷

These findings suggest that AA6216 may modulate lung fibrosis through SatM-associated mechanisms, including effects on monocyte accumulation and inflammatory mediator production. However, current evidence is limited to preclinical models, and additional studies are required to confirm efficacy, clarify mechanism, and establish relevance to clinical lung fibrosis (Table 1).⁷⁷

Table 1 Phosphodiesterase 4 (PDE4) Inhibitors Under Development for the Treatment of IPF and Inflammatory Diseases

Discussion

The pathogenesis of lung fibrosis, including idiopathic pulmonary fibrosis (IPF), involves a complex network of interactions among genetic background, environmental stimuli, and aberrant injury and repair responses. The disease is clinically characterised by progressive and largely irreversible deterioration of lung function, and median survival after diagnosis is commonly reported in the range of 3 to 5 years. Although the available standard therapies include antifibrotic agents such as nintedanib and pirfenidone, their principal benefit is to slow disease progression rather than reverse established fibrosis. In response to this therapeutic dilemma, phosphodiesterase (PDE) inhibition, particularly targeting PDE4 as a major cAMP-hydrolysing enzyme in relevant immune and structural cells, has attracted attention because it may offer combined anti-inflammatory and antifibrotic effects.

In this paper, we explored the potential mechanisms of PDE4 inhibition through the cAMP-PKA-CREB and EPAC signalling axes. By elevating intracellular cAMP, PDE4 inhibitors can suppress the production of pro-inflammatory mediators such as TNF-α and IL-1β through cAMP-dependent signalling. They may also influence profibrotic pathways, including TGF-β-associated fibroblast activation and myofibroblast differentiation, thereby providing multidimensional intervention in fibrotic remodelling. Because many of these pathways are context dependent, and evidence quality varies across experimental systems, mechanistic conclusions should be interpreted with appropriate caution.

At the translational level, the PDE4B-selective inhibitor nerandomilast has advanced the furthest in clinical development. In phase II studies, nerandomilast showed signals consistent with attenuation of lung function decline, including changes in FVC over the treatment period. Larger phase III programs were subsequently designed to evaluate longer-duration outcomes and to define safety and tolerability in broader patient populations. Mechanistic studies have suggested that subtype selectivity may reduce centrally mediated adverse effects observed with earlier PDE4 inhibitors, and may differentially modulate immune and mesenchymal cell phenotypes relevant to fibrotic progression. Importantly, direct comparative conclusions against other PDE4 inhibitors cannot be made in the absence of head-to-head randomised trials.

In parallel, several additional PDE4-directed strategies remain at an earlier stage. Roflumilast and other PDE4 inhibitors have shown antifibrotic signals in experimental models, including effects linked to inflammation, oxidative stress, and metabolic pathways. However, tolerability, dosing constraints, and uncertainty in clinical translation remain key considerations. Similarly, structurally novel candidates such as α-mangostin-derived PDE4 inhibitors and 2-arylbenzofuran derivatives have demonstrated antifibrotic-associated readouts in preclinical models. These findings are hypothesis generating and support continued medicinal chemistry and mechanistic refinement, but they require further validation in well-designed studies using clinically relevant endpoints. Overall, these advances reflect a shift from broad PDE4 inhibition toward approaches emphasising improved selectivity, tissue targeting, and an improved therapeutic index, which may help address persistent limitations in current antifibrotic therapy.

Summary

Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), is a chronic progressive interstitial lung disease characterised by a multidimensional pathological network involving dysregulation of the inflammatory microenvironment and activation of fibrotic remodelling processes. Based on the role of phosphodiesterase 4 (PDE4) in regulating cAMP signalling in immune and structural cells, PDE4 modulation has translational potential for interstitial lung remodelling diseases.

Clinical pharmacology studies in non-pulmonary indications have shown that PDE4 inhibitors, including apremilast and roflumilast, can provide anti-inflammatory efficacy with a safety profile that is generally manageable in appropriately selected patients. These agents may be relevant to lung fibrosis by modulating inflammatory pathways that have been implicated in fibrotic progression, including effects on Th17-associated signalling and other cytokine networks. However, the extent to which these mechanisms translate into clinically meaningful antifibrotic benefit in IPF remains to be established.

Translational research should prioritise evaluating the therapeutic potential of PDE4 inhibitors in pulmonary fibrosis. Randomised controlled trials are needed to confirm their impact on clinically relevant endpoints, including longitudinal lung function measures such as FVC decline. In parallel, pharmacokinetic and pharmacodynamic optimisation, including approaches that reduce centrally mediated adverse effects, will be important for improving the therapeutic index. At the basic research level, further study of subtype-selective PDE4 inhibitors, for example PDE4B-preferring strategies, may help clarify how cAMP signalling influences immune cell phenotypes, including macrophage activation states, within fibrotic lesions. In addition, exploring sequential or combination regimens of PDE4 inhibitors with existing antifibrotic agents (nintedanib and pirfenidone) may be informative, but such approaches require careful evaluation of safety, tolerability, and additive benefit in well-designed trials.

With ongoing development of inhaled PDE4 inhibitors and other lung-targeted delivery strategies, local drug delivery may reduce systemic exposure while increasing drug concentration in lung tissue. If supported by robust clinical evidence, these approaches could contribute to more individualised treatment strategies for lung fibrosis, including IPF.