Telomeres are six-nucleotide repeats located at the ends of chromosomes that prevent DNA degradation and fusion. The enzyme telomerase preserves this structure by maintaining and elongating telomeres. Increasing evidence indicates that telomere shortening and the consequent genomic instability are central drivers of fibrotic processes (30, 31). Although telomere attrition occurs as part of normal ageing, pathogenic variants in TRG accelerate this process and often result in premature shortening. Furthermore, different environmental factors may induce telomere attrition such as smoking and radiation. Once telomere length falls below a critical threshold—defined as under the 10th percentile for age (32)—DNA damage responses are triggered, leading to apoptosis (33), particularly in alveolar epithelial type II cells (AECII) (34).

The clinical spectrum associated with TRG variants is heterogeneous. Approximately 50% of individuals with TRG variants develop IPF, while others present with fibrotic HP (7–12%), CTD-ILD (2–3%), U-ILD (8–20%), or other idiopathic interstitial pneumonias (14–18%) (35, 36). Overall, TRG variants are identified in roughly one-quarter of FPF kindreds, with TERT variants accounting for 8–15% of cases (8, 36, 37), PARN and RTEL1 for 5–10% each (38), and TERC for 1–2% (36).

Importantly, short age-adjusted telomere length is not restricted to familial disease. It is found in around 50% of patients with FPF (38, 39), but also in sporadic ILD, including 20–60% of IPF (40, 41), 20–35% of fibrotic HP (42), and approximately 26% of RA-ILD (43). The mechanism leading to short telomere in those patients might include frequent variant in non-TRG and environmental risks factors (44). These findings underscore telomere dysfunction as a convergent pathogenic mechanism that extends across both familial and sporadic forms of ILD. Current evidence suggests that environmental exposures, particularly fine particulate air pollution (PM2.5), adversely affect patients with telomere dysfunction by promoting oxidative stress, genomic instability, and accelerated telomere shortening, thereby contributing to cellular senescence and pulmonary fibrosis progression. Recent studies further demonstrate associations between PM2.5 exposure, epigenetic alterations, and increased mortality in patients with fibrosing ILD (45).

Beyond the lung, telomere-related disorders exhibit incomplete penetrance and variable expressivity, which likely reflect the combined influence of environmental stressors, genetic background, and stochastic factors. A genetic anticipation phenomenon—characterized by earlier onset and more severe manifestations in successive generations—has also been observed in telomere biology disorder (TBD) due to progressive telomere shortening. Clinically, these entities are now recognized as part of a TBD, encompassing pulmonary fibrosis that may coexist with extrapulmonary involvement of variable severity, ranging from subtle laboratory abnormalities (such as premature greying, cytopenias or elevated liver enzymes) to overt organ failure (e.g., bone marrow failure, myelodysplastic syndrome/acute myeloid leukaemia or hepatic cirrhosis) (46).

Beyond their essential role in maintaining alveolar stability, surfactant proteins contribute to pulmonary host defense by regulating immune responses and inflammation. They constitute up to 10% of total surfactant weight and include five key proteins: SP-A1, SP-A2, SP-B, SP-C, and SP-D, encoded by SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD, respectively. Gene variants in SFTPA1, SFTPA2, SFTPB, and SFTPC are recognised monogenic causes of ILD and lung cancer (25, 47, 48).

Amongst these, SFTPB variants most frequently lead to severe neonatal respiratory failure, whereas SFTPA1, SFTPA2, and SFTPC genetic variation are implicated in both pediatric and adult ILD, particularly pulmonary fibrosis (49). In addition, gene variant involved in surfactant lipid transport, such as ABCA3 (ATP binding cassette subfamily A member 3), and regulatory genes including NKX2-1 (encoding thyroid transcription factor 1, TTF1), which governs transcription of both surfactant proteins and ABCA3, have also been identified (12). Collectively, these findings highlight disruption of surfactant homeostasis as a distinct group of monogenic causes of ILD (49).

From a clinical perspective, the identification of a rare surfactant gene variant in a proband has implications for family members. Genetic testing and radiological screening of unaffected individuals with pathogenic variants may enable early recognition of subclinical disease, providing opportunities for timely intervention and counselling (50).

Mucins (MUC) are gel-forming glycoproteins that constitute key components of airway mucus. The human genome encodes 17 mucins, of which MUC5AC and MUC5B are the most abundantly expressed in the airways (51). MUC5B, located on chromosome 11, encodes mucin 5 subtype B, a glycoprotein secreted by submucosal glands and airway secretory cells (51). It plays a central role in mucus production, mucociliary clearance, host defense, and the maintenance of airway and lung homeostasis (52).

Aberrant expression of MUC5B has been implicated in several respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (53), and severe community-acquired pneumonia (54). In the context of pulmonary fibrosis, excessive MUC5B production promotes mucus accumulation in the distal airways and impairs mucociliary clearance. This accumulation favours the retention of inhaled particles—such as cigarette smoke and air pollutants, both recognised risk factors for IPF—and contributes to epithelial injury. Moreover, excess MUC5B disrupts surfactant function and hampers AECII cell repair mechanisms (7). Collectively, these processes foster persistent epithelial damage, fibroproliferation, and honeycomb cyst formation, which are hallmark features of progressive pulmonary fibrosis (55).

Moreover, the MUC5B promoter variant rs35705950 is a strong genetic risk factor for rheumatoid arthritis-associated ILD (RA-ILD), particularly in patients with a UIP pattern and in familial forms of ILD. While this variant does not increase susceptibility to rheumatoid arthritis itself, it confers a markedly increased risk of ILD amongst RA patients, with effect sizes comparable to those observed in IPF (56).

TOLLIP encodes a ubiquitin-binding protein that regulates multiple steps of Toll-like receptor (TLR) signalling. It is expressed across diverse lung cell populations—including monocytes, macrophages, regulatory T cells, and alveolar epithelial type I cells—in both healthy individuals and patients with IPF (57). Four isoforms (A–D) have been identified; three are expressed in human mononuclear cells, where they modulate innate immune responses and influence epithelial cell apoptosis (57).

Through its roles in inflammation regulation, autophagy, and vacuolar trafficking, TOLLIP has been implicated in a broad range of pulmonary diseases, including IPF, COPD, asthma, and respiratory infections (57). In the context of IPF, SNPs within the TOLLIP locus on chromosome 11 have been associated not only with disease susceptibility but also with prognosis (58). These findings suggest that TOLLIP functions as both a regulator of innate immunity and a genetic determinant of interindividual variability in fibrotic lung disease.

Genetic variation in TOLLIP has been implicated in both susceptibility to pulmonary fibrosis and disease progression. While the minor C allele of TOLLIP rs5743890 appears protective against ILD development, it is paradoxically linked to worse survival and faster progression in established IPF. Other variants (rs111521887G, rs3750920T) increase ILD risk, though their prognostic impact is less consistent. Mechanistically, risk alleles are associated with reduced TOLLIP expression, enhanced epithelial apoptosis, and dysregulated innate immunity, promoting fibrotic remodelling (26).

Importantly, TOLLIP also has pharmacogenetic relevance, as IPF patients with the rs3750920 TT genotype benefit from N-acetylcysteine, whereas those with the CC genotype may experience harm, supporting a potential role for genotype-guided therapy; no such association has been observed with antifibrotic agents (59). In contrast, no association has been demonstrated between TOLLIP variants and response to antifibrotic agents such as nintedanib or pirfenidone (60).

Collectively, these findings indicate that TOLLIP genetic variants influence both disease susceptibility and progression in pulmonary fibrosis and may have therapeutic implications for NAC treatment, though not for antifibrotic therapies.

An important consideration in screening programmes for FPF is the potential impact on asymptomatic individuals. The identification of radiological, genetic, or biological abnormalities has been associated with feelings of regret and increased psychological burden amongst relatives who undergo screening (63). Consequently, any screening initiative should ideally be supported by appropriate multidisciplinary approach, including emotional, and decisions regarding testing must be accompanied by transparent and understandable about the implications of potential outcomes.

While prospective studies in FPF relatives are still lacking, practical recommendations can nonetheless be offered. These include minimising modifiable risk factors such as smoking, occupational exposures, and air pollution, as well as ensuring that vaccinations against respiratory pathogens are up to date. Indeed a recent prospective study showed that most relatives have at least one harmful respiratory exposure that may modified after genetic counselling (64). Although such measures do not replace future disease-modifying therapies, they may help reduce the risk of disease development or progression and remain relevant for improving overall health and resilience.

Genetic testing is most strongly indicated in patients with familial ILD, particularly those with two or more biologically related affected relatives, early-onset disease (<50 years), unusually severe or rapidly progressive disease, or syndromic features suggestive of a TBD. When testing is undertaken, the appropriate strategy is to begin with the index case or, in its absence, with an affected family member, as this increases the likelihood of identifying a segregating pathogenic variant. Testing unaffected relatives in the absence of this step may yield results that are challenging to interpret and of limited clinical value. It is important to recognise that only a positive genetic test result is unequivocally informative, but a negative result does not exclude genetic risk. To maximise diagnostic yield, testing should be reserved for patients with a high pre-test probability, as defined by clinical features and family history (65).

Importantly, screening strategies in FPF should not be limited to the detection of fibrosing lung disease. Given the multisystemic nature of telomere-related disorders, evaluation should also include potential extrapulmonary manifestations that may precede or accompany pulmonary fibrosis. Recognising these systemic features can improve early identification of at-risk individuals and refine risk stratification within affected families.

Moreover, about one-third of lung transplant recipients with PPF have telomere-dysfunction related to pathogenic TRG variants and/or short telomere length, and although carefully selected patients do not show consistently worse short- or mid-term outcomes compared with non-TRG variants/telomere shortening recipients, emerging evidence suggests that post-transplant care and treatment management may be more complex—given higher rates of complications such as CMV infection, cytopenias, and anastomotic problems—though definitive conclusions remain limited by heterogeneous data (66).

A positive result carries several potential implications. It may influence therapeutic decisions, such as transplant timing or the initiation of antifibrotic therapy; guide targeted screening of at-risk relatives; and support referral for specialised genetic counselling. These benefits must, however, be balanced against the limited variant interpretation, and the psychological impact of results. Together, these considerations highlight the need for multidisciplinary decision-making and careful integration of genetic testing into the broader clinical context of ILD.

In essence, successful FPF screening requires an integrated approach that combines clinical vigilance, preventive strategies, genetic counselling and psychological support, ensuring that early detection truly translates into meaningful patient benefit.

Given the growing recognition of FPF and the increasing availability of advanced imaging and genetic tools, the question of how and when to screen at-risk relatives has gained clinical relevance. Although high-quality evidence remains limited, recent studies and expert consensus provide a rationale for pragmatic, evidence-informed screening approaches.

A meticulous collection of the family history—ideally covering at least three generations—is a cornerstone of FPF evaluation. A detailed pedigree allows clinicians to identify inheritance patterns, anticipate variable disease expression, and guide genetic testing strategies. Importantly, family histories should be updated at each clinical visit, as new cases of interstitial lung disease or related extrapulmonary manifestations may emerge over time, refining the assessment of familial risk.

In this regard, the American Thoracic Society clinical statement presented evidence-based suggestions for evaluation and management of adults with ILA and a first-degree relative with pulmonary fibrosis (67). The evidence-based suggestions shown in Table 2 aim to guide clinicians in identifying ILA or ILD at early, potentially reversible stages (4, 10, 14, 62, 68–70). Together, these recommendations provide support to clinicians by standardizing the approach to ILAs. Although there are several important unanswered questions, it gives a direction for future initiatives, while emphasizing the need to identify treatment options for ILA.

The management of asymptomatic relatives of patients with FPF remains a major unresolved challenge. While many seek clarity regarding their individual risk, evidence is insufficient to define standardised protocols for screening or follow-up. Cohort studies indicate that a significant proportion of relatives may harbour ILA before symptoms emerge, yet predictors of progression are poorly understood (4, 14, 71). This uncertainty complicates decisions on the timing and intensity of surveillance and raises concerns about the psychological burden of monitoring individuals who may never develop clinically relevant disease.

HRCT scan is currently the most sensitive tool for detecting early ILD or ILA in at-risk relatives, though its optimal use remains debated. Critical questions—such as the appropriate age to begin screening, the interval between scans, and the management of indeterminate findings—remain unanswered. Moreover, HRCT entails radiation exposure and a risk of overdiagnosis or anxiety in otherwise healthy individuals (14). Emerging imaging technologies, including lung ultrasound and photon-counting computed tomography, may help address some of these limitations in the future. Pulmonary function tests, although insufficiently sensitive for early abnormalities detection, remain valuable for longitudinal monitoring once ILD is established (67).

A central limitation of the current landscape is that no single modality—imaging, lung function testing, genetic analysis, or biomarker measurement—can independently provide accurate prediction of disease risk. Future advances in FPF management will likely rely on integrated, personalized models that combine radiologic, physiologic, genetic, and molecular data. Such multidimensional approaches may enable early identification of high-risk individuals, refine surveillance strategies, and pave the way for preventive or early therapeutic interventions in FPF.

Ongoing research is increasingly focused on the discovery of biomarkers to refine risk stratification and disease monitoring. Shortened telomere length has been associated with a higher prevalence of ILAs and systemic manifestations (e.g., liver disease, bone marrow failure), although its limited sensitivity, specificity, and technical complexity currently preclude routine clinical use. Circulating biomarkers such as KL-6 have shown promise as indicators of alveolar injury and fibrotic activity, but their predictive value in asymptomatic relatives remains to be validated.

Notably, the PRECISIONS trial, which randomized patients with IPF carrying the TOLLIP rs3750920 TT genotype to receive oral N-acetylcysteine or placebo, demonstrated a pharmacogenetic interaction between N-acetylcysteine and the TOLLIP polymorphism, highlighting the critical need for molecularly guided, personalized therapeutic strategies and randomized clinical trials and representing an important step towards precision medicine in fibrotic ILD (72).