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Open research questions in Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

70 unresolved questions extracted from the limitations and future-work sections of 307 Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Introduction Fibroblast activation protein (FAP)-targeted radiopharmaceuticals have been widely applied in oncologic imaging and therapy, while their application in pulmonary fibrosis remains underexplored.

    Targeted depletion of activated fibroblasts via [177Lu]Lu-FAPI radionuclide therapy ameliorates bleomycin-induced lung fibrosis · 2026 · DOI

  • Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options and poorly understood molecular underpinnings.

    FXR-mediated recruitment of PPP1CB suppresses SMAD2/3 phosphorylation to mitigate pulmonary fibrosis · 2026 · DOI

  • While the roles of several cysteine proteases have been documented, the specific contribution of cathepsin V (CatV) and legumain (LGMN) remains poorly explored.

    Legumain (asparaginyl endopeptidase) modulates extracellular matrix dynamics in pulmonary fibrosis · 2026 · DOI

  • ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction and defective regeneration, yet the matrix‐derived factors contributing to this process remain poorly defined.

    Targeting Elastin‐Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease · 2026 · DOI

  • Results CIP research was sparse before 2015, increased after 2015, and accelerated after 2019, with the highest annual output observed in 2023.

    Diagnostic research in immune checkpoint inhibitor-related pneumonitis: a bibliometric analysis of research evolution, diagnostic focuses, and future priorities · 2026 · DOI

  • Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear.

    Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity · 2026 · DOI

  • Currently, very little is known about the steps involved in disease initiation and progression because models of IPF poorly replicate these processes.

    Modeling cell-cell interactions to advance drug discovery in Idiopathic Pulmonary Fibrosis · 2026 · DOI

  • BackgroundThis study aimed to elucidate B cell subset pathology in COPD, a poorly characterized area, with a focus on its similarities to and differences from classical autoimmune disorders.

    IgG4⁺ plasma cell enrichment and {lambda}-chain-biased BCR remodeling drive low-grade autoimmunity in chronic obstructive pulmonary disease · 2026 · DOI

  • Pirfenidone and curcumin show promising binding affinity with these hub gene-encoded proteins, providing a theoretical basis for further investigation into lactylation-targeted therapeutic strategies in IPF.

    Identification and functional validation of lactylation-related hub genes in idiopathic pulmonary fibrosis based on multi-omics analysis · 2026 · DOI

  • Although PFT parameters showed meaningful clinical associations, their ability to discriminate hrCT-confirmed ILD was limited within this clinically pre-selected population, indicating that spirometry and DLCO are insufficient as standalone tools for ILD identification in hrCT- referred patients.

    Real-world Screening for Interstitial Lung Disease in Rheumatoid Arthritis: The Value of Spirometry, DLCO, and Clinical Risk Factors · 2026 · DOI

  • The fibroblast-to-myofibroblast-transition (FMT) and metabolic reprogramming of lung fibroblasts (HLFs) are essential to IPF pathogenesis, yet the connection between nutrient metabolism and fibrogenesis remains poorly defined.

    O-GlcNAc transferase regulates H2O2 production via p38 MAPK · 2026 · DOI

  • Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood.

    Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis · 2026 · DOI

  • Gastroesophageal reflux disease (GERD) is increasingly recognized as a common comorbidity in ILD, particularly in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD), though its clinical significance remains incompletely understood.

    State of the Art: The Relationship Between GERD and Interstitial Lung Disease · 2026 · DOI

  • This study used a claims-based definition of IPF. The presence of a diagnosis code in claims did not guarantee presence of disease; however, we sought to overcome this potential limitation by requiring a confirmatory diagnosis, thereby limiting misidentification of IPF patients. Patients without an IPF diagnosis in the 12-month baseline were considered newly diagnosed. Patients with IPF may not have sought care for their condition during that 12-month period and may have been misclassified as newly diagnosed; however, this seems unlikely given the frequency with which the IPF cohort received services during follow-up. To be included in this study, patients had to be enrolled in a health plan (ie, commercial or MAPD) during the study period; thus, findings from this study may not be generalizable to all patients with IPF, particularly those without insurance or those without continuous enrollment. This study minimized bias by utilizing exact matching on baseline demographic variables and adjusting for additional covariates, including baseline comorbidities, in regression analyses to examine outcomes of interest; however, residual and unobserved confounding could not be ruled out. There were inherent limitations to the use of a claims database for research, as medical and pharmacy claims were collected for the purpose of payment. Coding errors may have resulted in inaccurate or incomplete data, leading to potential misclassification of variables of interest and bias in research findings. A claim for a prescription was not an indication the medication had been consumed or taken as prescribed. Physician-provided samples, medications taken as part of a clinical trial or over-the-counter medications could not be observed in claims data. Despite these limitations, claims data provided a robust and valuable source for the real-world examination of outcomes. Finally, the observed cost differences between the IPF cohort and the demographically matched comparator cohort should not be interpreted as fully attributable to IPF itself, nor do these results imply that IPF-specific treatment alone would be sufficient to eliminate the observed differences.

    Real-World Health Care Resource Utilization and Economic Burden Among Patients with Idiopathic Pulmonary Fibrosis in Commercially Insured and Medicare Advantage Populations in the United States · 2026 · DOI

  • Future research should focus on screening suitable excipient systems to ensure the chemical integrity of active ingredients during stor- age and use. Furthermore, although the pivotal roles of Pi3k and Tlr4 in PF have been established, the regulatory mechanisms of their active subunits remain unexplored. While this study suggests that RCEO may mitigate PF by inhibiting the recruitment of circulat- ing monocytes to injured lung tissue via the Tlr4/Myd88/ Nf-κb pathway, the underlying mechanisms of interven- tion warrant further investigation.

    Exploring the role of RCEO in macrophage-mediated modulation of pulmonary fibrosis · 2026 · DOI

  • The mechanistic link between elevated SII components (neutrophils, platelets, lymphopenia) and specific fatal complications (infections, multi-organ failure, metabolic imbalance) in ILD has not been empirically investigated; direct measurement of pro-fibrotic mediators, platelet-derived growth factors, and immune exhaustion markers alongside systemic immune-inflammation index is needed.

    Linear association between the systemic immune-inflammation index and all-cause mortality in patients with interstitial lung disease: a retrospective cohort study · 2026 · DOI

  • Existing studies on SII in ILD have focused on disease progression rather than mortality with relatively short follow-up periods; long-term prospective cohort studies with extended follow-up duration are needed to comprehensively assess the independent association between systemic immune-inflammation index and all-cause mortality outcomes.

    Linear association between the systemic immune-inflammation index and all-cause mortality in patients with interstitial lung disease: a retrospective cohort study · 2026 · DOI

  • Patients with diverse etiological backgrounds and multiple ILD subtypes were largely analyzed together without detailed subtype-specific classification; the context-dependent biological implications of systemic immune-inflammation index across autoimmune-driven versus non-immune-driven interstitial lung disease subtypes requires stratified analysis.

    Linear association between the systemic immune-inflammation index and all-cause mortality in patients with interstitial lung disease: a retrospective cohort study · 2026 · DOI

  • Translation of therapeutic candidates will require rigorous pharmacology and specificity assessment, including promiscuity/PAINS considerations, ADME profiling, and experimental validation in relevant cellular and in vivo fibrosis models.

    Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation · 2026 · DOI

  • Precise targeting of fibroblasts or specific DAMP–TLR4 interactions may be more effective, but a universal inhibition of TLR4 may not be appropriate, requiring cell type- and ligand-dependent validation.

    Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation · 2026 · DOI

  • The exact mechanism and correlation of this clinical course remains unknown; however, it is clear that the pulmonary fibrosis is caused by COVID-19 pneumonia.

    Rapidly progressive pulmonary fibrosis in COVID-19 pneumonia · 2021 · DOI

  • The study is limited to a single case presentation; larger-scale studies with multiple patients are needed to validate the efficacy of smoking cessation as monotherapy in DIP.

    “Desquamative Interstitial Pneumonia” with Early Diagnosis · 2019 · DOI

  • The paper does not establish clear clinical guidelines or criteria for determining when steroid treatment should be initiated versus when smoking cessation alone is sufficient for DIP patients.

    “Desquamative Interstitial Pneumonia” with Early Diagnosis · 2019 · DOI

  • Although the clinical significance of these early epithelial changes detected by serum CC16 remains to be determined, these results clearly show that the assay in serum of lung secretory proteins such as CC16 represents a new noninvasive approach to evaluate the integrity of the respiratory tract.

    Clara Cell Secretory Protein (CC16): Features as a Peripheral Lung Biomarker · 2000 · DOI

  • Future research is required to elucidate the precise mechanisms underlying MPT0E028’s antifi- brotic effects and to determine its potential therapeutic applications in pulmonary fibrosis.

    MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM/AMPK/FoxO1 pathway · 2026 · DOI

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70 open questions have been extracted from the limitations and future-work passages of 307 Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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