Genetic constituents serve as fundamental drivers in the initiation and evolution of IPF (Ballester et al., 2019). A growing body of evidence indicates that susceptibility to IPF is linked to a complex interplay of genetic variations and alterations in transcriptional activity (Wolters et al., 2018). Mutations in the mucin 5B gene have emerged as one of the most influential risk factors for IPF (Wang et al., 2022). A pivotal study unveiled a prevalent single nucleotide polymorphism in the promoter domain of the MUC5B gene on chromosome 11 (Stainer et al., 2021), predominantly associated with pulmonary fibrosis (Biondini et al., 2021). Telomeres, non-coding, repetitive nucleotide sequences situated at chromosome extremities, shield chromosomes from progressive attrition during typical cellular replication (Drakopanagiotakis et al., 2018). Rare aberrations in genes associated with telomere homeostasis have been strongly implicated in pulmonary fibrosis (Wells et al., 2018). It has been observed that nearly all sporadic IPF patients present shortened telomeres in alveolar epithelial cells (Sgalla et al., 2018). Furthermore, both acute and chronic fibrotic lung diseases transpire in patients with mutations in pulmonary surfactant apolipoprotein and lipid transporter (Plantier et al., 2018), insinuating a significant role of surfactant composition or metabolic alterations in IPF.

Frequently, particulate matter, fibers, and dust constitute the primary environmental contributors to IPF onset (Phan et al., 2021). A noteworthy surge in IPF incidence is observable among individuals with exposure to animal dust, chemical fumes, metal dust (including lead and steel), and other pollutants (Walters, 2020). These contaminants are identified as precipitators of oxidative stress, epithelial damage, and airway inflammation (Sack and Raghu, 2019). Studies suggest that air pollution may incite epigenetic modifications in the lung, enhancing pathogenicity in synergy with other antigens (Park et al., 2021), and potentially initiating or fostering disruptions in alveolar damage and repair mechanisms. Post-mortem examinations of IPF patients have detected inorganic particles in lung lymph nodes (Collins et al., 2018), further corroborating the environmental exposure etiology.

Recent investigations underscore the crucial role of microbiota in inciting and exacerbating pulmonary fibrosis in animal models, thereby elucidating the association between microbiota and pulmonary fibrosis (Spagnolo et al., 2019). Contemporary characterizations of the respiratory microbiota in IPF suggest that an escalated bacterial burden and the presence of specific organisms may be instrumental in disease onset (Molyneaux et al., 2014). Some viruses have also been implicated in initiating, promoting, or intensifying IPF (Phan et al., 2021). Bacteria and viruses can inflict damage on airway epithelial cells directly or indirectly through the activation of immune responses to infection (Sack and Raghu, 2019). Evidence indicates that extracellular vesicles generated by certain Gram-negative bacteria, resulting from lung microbiota dysregulation, instigate the expression of pro-inflammatory and pro-fibrotic genes across a variety of cell types. Additionally, IL-17B and TNF-a secreted by these extracellular vesicles interact to construct an inflammatory network system conducive to pulmonary fibrosis (Yang et al., 2019). Research conducted by David and colleagues unveiled a significant correlation between the lung microbiota burden and IPF progression (O'Dwyer et al., 2019). Furthermore, it has been reported that the mortality risk in IPF escalates with the increasing bacterial burden in the lung (Molyneaux et al., 2014).

Recognized as a principal risk factor for chronic respiratory diseases such as COPD (Aghapour et al., 2018), smoking also has a significant role in precipitating pulmonary fibrosis. A potent correlation exists between smoking and IPF, which amplifies with the escalation in dosage, especially evident in habitual smokers or those who have smoked over extended periods (Bellou et al., 2021). Cigarette smoke can inflict damage on all lung cell types, particularly alveolar epithelial cells, giving rise to diffuse infiltration and parenchymal fibrosis (Kumar et al., 2018). One investigation indicated that IPF patients with a long-term smoking history exhibited lower overall cell density, albeit higher alveolar cell density and more severe damage (Zhang et al., 2021). One study established that cigarette smoking correlates with an augmented risk of IPF, with ever-smokers facing a 60% elevated risk (Bae et al., 2022).

The pronounced incidence of gastroesophageal reflux disease (GERD) in IPF suggests a pathogenic role for microaspiration attributable to GERD (Bedard Methot et al., 2019). Chronic microaspiration stemming from GERD is deemed a likely precursor to IPF (King and Nathan, 2017). For individuals predisposed to IPF, chronic microaspiration induced by gastric reflux can inflict enduring, recurrent damage to lung tissue, increasing lung epithelial cell permeability, continually stimulating pulmonary fibrosis proliferation, and eventually contributing to the manifestation of pulmonary fibrosis (Ghisa et al., 2019). Several cell biology experiments and preclinical studies indicate that gastric reflux constituents, such as acid and proteases, can elicit adverse effects such as immune response stimulation, enhanced cell membrane permeability, severe airway inflammation, and lung tissue structure alteration (Nelkine et al., 2020). Evidence supporting this hypothesis emerges from descriptive studies conducted in both experimental animal models and humans (Chen et al., 2019; Reynolds et al., 2023).

The mechanism by which aging leads to pulmonary fibrosis remains unclear. Cellular senescence can disrupt various cellular biological activities in the body, manifesting as telomere attrition, DNA damage, and mitochondrial dysfunction (Merkt et al., 2020). Research indicates that cellular senescence induced by telomere degradation primarily afflicts alveolar epithelial type II cells, which is intricately linked to IPF pathogenesis (Stuart et al., 2014; Selman et al., 2019). Repeated microdamage to senescent epithelial cells in genetically susceptible individuals can trigger abnormal fibroblast activation, culminating in ECM accumulation and fibrosis (Pardo and Selman, 2016). Multiple murine models of pulmonary fibrosis display evidence of various cellular senescence markers, including heightened aging-associated β-galactosidase in lysosomes, an increased BCL-2/Bax ratio of apoptosis-involved proteins in mitochondria, and amplified DNA damage in the nucleus (Schafer et al., 2017; Blokland et al., 2020), all coupled with robust pro-fibrotic effects, such as TGF-β (Rana et al., 2020). Aging can impede stem cell turnover functionality, obstructing the repair and regeneration of alveolar epithelial cells in damaged lungs (Mei et al., 2021). Aging has been implicated in promoting fibrosis by thwarting blood vessel regeneration (Chen et al., 2021). IPF prevalence and incidence continue to rise in individuals over 65 years and remain exceedingly rare in those under 50 years old (Raghu et al., 2018), reinforcing the classification of IPF as an aging-related disease.

TGF-β is considered a central component among the diverse factors contributing to pulmonary fibrosis development (Chanda et al., 2019). Released in response to epithelial cell injury, TGF-β acts as a key upstream pro-fibrotic growth factor propelling the disease’s pathophysiology (Shimbori et al., 2019; He et al., 2021b). As a multifunctional cytokine, TGF-β fosters pulmonary fibrosis through a range of mechanisms (Nolte and Margadant, 2020). Primarily, it incites the proliferation and differentiation of epithelial cells and fibroblasts (Ghavami et al., 2018), spurs myofibroblasts to generate the extracellular matrix, catalyzes epithelial-mesenchymal transition, expedites epithelial apoptosis and cell migration, and provokes the production of connective tissue growth factor among other mediators (Phan et al., 2021). TGF-β not only choreographs the congregation of fibroblasts at injury sites but also facilitates their metamorphosis into myofibroblasts (Ye and Hu, 2021). Moreover, TGF-β distinguishes itself as the most efficacious extracellular matrix production stimulant and is considered the strongest chemoattractant for immune cells, including monocytes and macrophages (Kinoshita and Goto, 2019).

The insulin-like growth factor has a significant role in pulmonary fibrosis progression (Kheirollahi et al., 2022). Composed of 70 amino acids, IGF-1 chiefly mediates a range of biological functions, including cell division, differentiation, apoptosis, and metabolism (Jensen-Cody and Potthoff, 2021; Jiang et al., 2023). IGF-1 is postulated to facilitate fibroblast proliferation, migration, and differentiation, augmenting the ability of fibroblasts to synthesize fibronectin and collagen, thereby boosting ECM deposition (Renaud et al., 2020). This leads to scarring, resulting in stiffness, the loss of standard lung architecture, and, ultimately, compromised lung function. Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of pulmonary fibrosis by contributing to myofibroblast generation. Studies indicate that IGF promotes the pro-fibrotic milieu chiefly through IGF1R signaling pathways, by suppressing matrix metalloproteinases, up-regulating TGFβ, and secreting tissue metalloproteinase inhibitors (Garrett et al., 2019). Further research has shown that TGF-β is crucial for IGF-1 induction in myofibroblasts, and increased levels of IGF-1 in IPF tissues are associated with diminished lung function during disease progression (Hernandez et al., 2020). Mice with bleomycin-induced lung fibrosis and human IPF lung tissue have exhibited elevated IGF-1 levels (Sun et al., 2021). IGF-1 invigorates fibroblast proliferation, protects myofibroblasts from apoptosis, and advocates ECM accumulation, all of which are integral processes in pulmonary fibrosis. Hence, IGF-1 occupies a vital role in the onset and/or proliferation of pulmonary fibrosis.

CTGF, or CCN2, is recognized as a prolific instigator of chronic fibrosis hyperplasia (Sgalla et al., 2020a; Effendi and Nagano, 2022). As a cysteine-rich stromal cell protein, it exerts influence over numerous biological processes, including cell proliferation, differentiation, adhesion, angiogenesis, and multiple pathological processes such as tumorigenesis and tissue fibrosis (Ungvari et al., 2017). CTGF is a primary mediator of TGF-β-induced pulmonary fibrosis (Yanagihara et al., 2022). The activation mediated by TGF-β response elements within the CTGF promoter instigates CTGF production, thereby affirming it as a principal arbitrator of TGF-β-induced pulmonary fibrosis (Nguyen et al., 2018). Frequently expressed in mesenchymal cell lines, CTGF often directs tissue regeneration and pathological fibrosis formation via ECM deposition, fibroblast proliferation, and matrix generation (Ramazani et al., 2018). Indeed, the utilization of anti-CTGF antibodies in fibrotic animal models attenuates ECM component expression, enhances survival post-radiation-induced lung injury, and conserves the morphology of alveolar epithelial cells (Bickelhaupt et al., 2017). In IPF patients, CTGF expression is elevated in alveolar cells and mesenchymal fibroblasts (Kasam et al., 2020).

MMPs are proactive contributors to pulmonary fibrosis (Todd et al., 2020). This family of endopeptidases, including MMP-3, MMP-7, and MMP-8, is integral to regulating EMT degradation in IPF (Roque et al., 2020b; Bormann et al., 2022). EMT activation in the lungs is believed to be one of the mechanisms associated with the loss of alveolar cells and the formation of pulmonary fibrosis. These MMPs facilitate pulmonary fibrosis development via several mechanisms: 1. Fostering epithelial-mesenchymal transition (Liu et al., 2020); 2. Inducing m acrophage polarization (Le et al., 2020); 3. Propelling fibroblast migration (Menou et al., 2018); 4. Encouraging abnormal epithelial cell migration and other irregular repair processes (Drankowska et al., 2019). MMP-7 expression is enhanced in both human IPF and mouse fibrosis models (Mahalanobish et al., 2020; Probst et al., 2020). Research has demonstrated that mice with MMP-3 deletion or MMP-7 knockout are safeguarded from bleomycin-induced fibrosis (Mahalanobish et al., 2020). IPF patients exhibit elevated MMP levels in alveolar lavage fluid and blood (Inoue et al., 2020; Espindola et al., 2021). Clinical data suggest an association between elevated MMP-7 levels and an increased risk of mortality and disease progression (Khan et al., 2022).

Exosomes are phospholipid bilayer membranous vesicles, measuring between 30 and 150 nm (Negrete-Garcia et al., 2022). Continuously secreted by a variety of cell types, they transport biologically active substances such as proteins, lipids, and genetic material (DNA, mRNA, miRNAs, and lncRNAs) (Yang et al., 2022). Bronchial epithelial cells primarily generate exosomes in the lungs, which activate fibroblasts, stimulate their differentiation into myofibroblasts, and catalyze excessive extracellular matrix component deposition (Abreu et al., 2021). By delivering miRNA to recipient cells, exosomes regulate diverse inflammatory and angiogenic pathways, playing an instrumental role in inflammation, tissue repair, and fibrogenesis (Rasaei et al., 2022). A multitude of studies underscore the significance of exosomes in IPF pathogenesis, particularly regarding epithelial phenotypes and fibroproliferative responses (d'Alessandro et al., 2021a; Martin-Medina et al., 2018; Parimon et al., 2019). Studies indicate an upregulation of miR-21 in exosomes in mouse pulmonary fibrosis models and human IPF patient serum, correlating with disease progression and mortality (Pastor et al., 2021). A recent study reported an elevated number of Wnt5a-carrying exosomes in IPF patients. These lung fibroblast-derived exosomes exert an autocrine effect, stimulating in vitro fibroblast proliferation (Baarsma and Konigshoff, 2017).

To summarize, the pathogenesis of idiopathic pulmonary fibrosis is complex, with specific mechanisms appearing to intersect with each other, as outlined in this paper, is depicted in Figure 1.

Historically, chronic inflammation, seemingly uncontrollable, was perceived as the primary driver of progressive parenchymal fibrosis development (Behr, 2013). Systemic steroids, due to a dearth of effective alternatives, served as the standard treatment for IPF (Raghu et al., 2015). Combinatorial immunosuppressants, including prednisone, azathioprine, cyclophosphamide, and acetylcysteine, were similarly efficacious (Walter et al., 2006). Glucocorticoids and immunosuppressants are usually used for empirical treatment of acute exacerbation of idiopathic pulmonary fibrosis (Naccache et al., 2022). Some studies have shown that the combination of them is beneficial in prolonging the survival of acute patients (Yamazoe and Tomioka, 2018). However, there is currently insufficient evidence to support their routine use. An increasing number of clinical trials have shown that anti-inflammatory therapy and immunosuppressive agents are not effective in conventional treatment of IPF (Ryu et al., 2014; Barratt et al., 2018), leading to the discontinuation of their recommendation for the routine treatment of IPF.

Pirfenidone, the inaugural oral antifibrotic drug to receive approval, is a pyridine derivative widely recognized for the treatment of IPF (Vancheri et al., 2018). Its mechanism of action, while multifaceted, remains incompletely understood. Pirfenidone exhibits anti-inflammatory, anti-oxidative, and anti-fibrotic properties, thereby reducing collagen synthesis and deposition in the lungs (Saito et al., 2019). By inhibiting the cytokine TGF-β, it curtails the proliferation, differentiation, and collagen secretion of human lung fibroblasts, decelerates the fibrotic process, and attenuates the decline rate of forced vital capacity (FVC) (Aimo et al., 2022). Several animal model studies in recent years have corroborated the antifibrotic characteristics of pirfenidone (Carrington et al., 2018). It can enhance the prognosis of IPF, reduce mortality, and prolong progression-free survival (Nathan et al., 2017; Vancheri et al., 2018), as has been demonstrated in numerous randomized, placebo-controlled phase III trials (King et al., 2014; Noble et al., 2016). In IPF treatment, pirfenidone demonstrates not only tolerability but also a desirable safety profile (Veit et al., 2019). Therefore, pirfenidone presents a promising treatment avenue for IPF.

Nintedanib, another approved oral antifibrotic drug, operates as an orally active triple tyrosine kinase receptor inhibitor (Molina-Molina, 2019). Originally conceived as an anti-cancer drug, it later displayed antifibrotic effects and received approval for IPF treatment (d'Alessandro et al., 2021b). Nintedanib effectively impairs the activity of platelet-derived growth factor receptor kinase, fibroblast growth factor receptor kinase, and vascular endothelial growth factor receptor kinase (Hilberg et al., 2008). It suppresses the release of pro-inflammatory and pro-fibrotic mediators, inhibits fibroblast migration and differentiation, and contributes to the blockade of extracellular matrix deposition (Wollin et al., 2015). In bleomycin-induced animal pulmonary fibrosis models, nintedanib exhibited antifibrotic, anti-inflammatory, and vascular remodeling activities (Ackermann et al., 2017). Phase 3 clinical trials demonstrated that, compared to a placebo, nintedanib significantly attenuates the decline rate of forceful lung volume following mild to moderate lung function impairment in IPF patients (Collins and Raghu, 2019). Nintedanib significantly mitigated the risk of disease progression and also demonstrated a mortality-reducing benefit (Richeldi et al., 2014). Moreover, nintedanib exhibited a manageable safety and tolerability profile in clinical trials involving patients (Seibold et al., 2020).

Lung transplantation presents itself as the sole treatment alternative that can enhance the quality of life and augment survival rates when previous treatments have failed to yield positive outcomes (Balestro et al., 2019). This life-saving procedure serves as the ultimate solution for advanced stages of IPF. After the diagnosis of IPF, the lung transplantation should be actively evaluated to start the early implantation of transplantation concept. Candidates typically considered for lung transplantation are those with limited treatment alternatives and face a death risk exceeding 50% within 2 years without the transplantation (George et al., 2019). The survival rate post-transplantation has shown consistent improvement over the years, with recent statistics indicating a 1-year survival rate of 88.8% and a 5-year survival rate of 59.2% (Valapour et al., 2021). Despite the continual enhancement in the overall prognosis of lung transplantation, it remains a complex procedure for IPF laden with potential complications. Limitations in the procedure’s application arise from the scarcity of donor organs, the possibility of acute graft-versus-host disease, and the risk of infection (Kapnadak and Raghu, 2021).