Proteomic Biomarkers Hold Promise in IPF

Proteomic mass spectrometry can unlock important biomarkers with prognostic and diagnostic value in idiopathic pulmonary fibrosis (IPF) and help deepen scientists’ understanding of the disease’s development, according to a new review.1

Writing in the journal Biomedicines, corresponding author Anna Valeria Samarelli, PhD, of the University Hospital of Modena, Italy, and colleagues said proteomics have significant clinical relevance in IPF, and the advancement of mass spectrometry has helped to make such insights more accessible.1

One reason mass spectrometry-based proteomics is particularly exciting is that the use of AI can greatly enhance peptide and protein identification and therefore quantification accuracy. | Image credit: lexiconimages - stock.adobe.com

A major challenge in treating IPF, the authors noted, is its unpredictability. That unpredictability, they noted, is one reason the disease has poor survival rates, even with the development of drugs like pirfenidone (Esbriet; Legacy Pharma) and nintedanib (Ofev; Boehringer Ingelheim), which can slow the progression of IPF. A study published earlier this year found just one-third of patients survived more than 5 years after diagnosis.2

The authors said mass spectrometry-based proteomics can be particularly helpful because it can profile the entirety of the proteome, including post-translational modifications, protein degradation, and dynamic expression changes.1

“These features are especially relevant in IPF, where aberrant protein signaling, ECM (extracellular matrix) remodeling, and acute inflammatory events are hallmarks of disease progression and acute exacerbations,” they said.

The investigators added that mass spectrometry-based proteomics is advantageous because it can be performed noninvasively, using bronchoalveolar lavage fluid (BALF), serum, and plasma.

For instance, the investigators said the serum biomarker matrix metalloproteinase-7 (MMP-7) has been shown to be a “robust and reproducible” circulating biomarker in IPF. Evidence suggests it may help distinguish between healthy patients and those with lung disease. It may even help clinicians distinguish between IPF and other types of lung disease, such as chronic obstructive pulmonary disease (COPD), they said.

A number of biomarkers have been shown to be differentially expressed in the BALF of patients with IPF, including MMP7, as well as C-X-C Motif Chemokine Ligand 7 (CXCL7) and C-C Motif Chemokine Ligand 18 (CCL18). Research comparing patients with IPF to healthy controls and to those with a history of smoking has helped to identify other potentially important differences in the protein profiles of patients with IPF, they said.

Proteomics can also identify biomarkers in lung tissue and pulmonary cell lines, the authors noted.

Overall, the most frequently reported biomarkers include MMP-7, CCL18, Krebs von den Lungen-6 (KL-6), and Surfactant Protein D (SP-D). Those biomarkers have been linked with a number of features of IPF, including ECM remodeling and inflammatory signaling. MMP-7 has also been associated with disease severity and progression in multiple studies, though its expression patterns are not unique to IPF and therefore it may not be sufficiently specific to serve as a reliable independent biomarker, the authors said. The matricellular protein periostin is also seen as a promising biomarker, though the investigators said it has not been studied enough to be considered a strong biomarker.

One reason mass spectrometry-based proteomics is particularly exciting, Samarelli and colleagues said, is that the use of artificial intelligence (AI) can greatly enhance peptide and protein identification and therefore quantification accuracy.

“AI-driven computational and predictive models enhance proteomic workflows for biomarker discovery, identifying protein expression profiles that specifically discriminate between healthy and disease states in various medical fields, such as cardiovascular diseases, cancer, and neurodegenerative diseases,” they wrote.

AI is already being integrated into proteomics research, the authors noted, though they said it will require significant investment and regulatory guidance.

Still, the investigators said it will be important that efforts are made to drive down the cost of proteomics in order to make it useful in the clinical setting. They said there is also a limited awareness of the value of mass spectrometry technologies within the clinical community, a factor that also limits its use. Many studies have helped lay the groundwork for proteomics-based biomarkers to play a key role in the treatment of IPF, they concluded, but more work is needed before that work can be fully integrated into the clinic.

References

1. Raineri G, Samarelli AV, Tonelli R, et al. Predicting and treating pulmonary fibrosis with proteomic biomarker investigations. Biomedicines. 2025;13(11):2656. doi:10.3390/biomedicines13112656

2. Kim HJ, Weber JM, Neely ML, et al. Predictors of long-term survival in patients with idiopathic pulmonary fibrosis: data from the IPF-PRO registry. Lung. 2025;203(1):40. doi:10.1007/s00408-025-00797-4