Researchers ID 4 gene biomarkers that could help in early IPF diagnosis
With common symptoms, disease typically is diagnosed only after lung damage
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Activity levels of four genes linked to the Notch signaling pathway — which helps regulate cell growth, tissue repair, and immune responses in the body — may serve as blood-based biomarkers that could aid in the early diagnosis of idiopathic pulmonary fibrosis (IPF).
Those are the findings of a new study by researchers in China, who focused on the Notch signaling pathway amid growing evidence suggesting it plays a role in fibrosis, or scarring that typically damages the lungs.
The team determined that four genes, namely IL4, PLXND1, NBEA, and GATA2, may have diagnostic potential in IPF.
“IL4, PLXND1, NBEA and GATA2 show promise as biomarkers for the future treatment of fibrotic diseases, providing new avenues for exploration,” the researchers wrote, emphasizing, however, that their findings are preliminary and require further validation.
The study detailing their findings, titled “Identification of Notch pathway-related biomarkers in patients with idiopathic pulmonary fibrosis,” was published in the journal PLOS One.
IPF, a type of pulmonary fibrosis, is a chronic condition in which scar tissue progressively builds up in the lungs. Over time, this scarring, or fibrosis, can damage lung structures, reduce lung function, and ultimately lead to respiratory failure and death.
IPF, like other diseases, is marked by shortness of breath, persistent cough
The researchers noted that, because early symptoms such as shortness of breath and persistent cough can resemble those of other conditions, IPF is often diagnosed late, when lung damage is already advanced.
Antifibrotic medications approved for IPF, including pirfenidone (sold as Esbriet and generics) and Ofev (nintedanib), can slow the decline in lung function but cannot stop or reverse the disease.
“Therefore, identifying novel biomarkers and elucidating the molecular mechanisms underlying IPF will aid in improving diagnosis, guiding targeted drug development, and enhancing clinical management of the disease,” the researchers wrote.
To identify potential biomarkers, the team analyzed gene activity in blood samples from people with the condition and healthy individuals who served as controls, using two publicly available datasets.
The first dataset (GSE28042) had blood samples from 75 people with IPF and 19 healthy controls and was used to identify disease-associated genes. That analysis identified 1,361 genes whose activity was different in IPF patients compared with healthy individuals. Of these, 548 genes were more active and 813 genes were less active in people with IPF.
Researchers ID 4 gene biomarkers that could help in early IPF diagnosis
The researchers then focused on Notch pathway-related genes (NPRGs). By combining the differentially expressed genes with IPF-associated gene networks and a predefined list of Notch pathway-related genes, the team narrowed the analysis to seven Notch-related candidate genes.
Next, the scientists used machine learning tools — computer programs designed to identify patterns in large datasets — to determine which genes best distinguished IPF patients from healthy controls. Two independent models highlighted the same four genes, namely, IL4, PLXND1, NBEA, and GATA2, pointing to their potential diagnostic value.
IL4 can drive immune cells called macrophages into a state commonly associated with profibrotic immune responses, while PLXND1 can trigger signals that promote tissue scarring. GATA2, when disregulated, may lead to excessive activation of fibroblasts and reduce the ability of immune cells to clear damaged tissue, potentially worsening lung fibrosis.
NBEA is a tumor-suppressor gene whose mutations have been linked to cancer-related activation of fibroblasts, which are cells that help repair tissue but can cause scarring when they become overactive. Based on these findings, the authors suggested that NBEA may also play a role in lung fibrosis.
A diagnostic model based on these four genes accurately identified IPF patients from healthy controls in the first dataset. When tested in a second, independent dataset (GSE38958), which comprised 70 people with IPF and 45 healthy controls, the model showed more modest diagnostic performance.
Further analyses showed that IL4, NBEA, and GATA2 were associated with higher levels of dendritic cells and lower levels of follicular helper T cells, immune cells involved in regulating inflammation and previously linked to immune dysregulation in IPF. PLXND1 showed the opposite pattern and was positively correlated with monocytes, immune cells previously associated with IPF severity.
“Therefore, it is hypothesized that IL4, GATA2, NBEA, and PLXND1 may influence IPF development by regulating these immune cell populations,” the team wrote.
Findings tested in IPF patients and healthy volunteers
To confirm their findings, the team measured gene activity levels directly in blood samples from people with IPF and healthy volunteers. The results showed that IL4 and NBEA levels were significantly reduced, while PLXND1 levels were significantly increased, in people with IPF. GATA2 showed a similar trend but did not reach statistical significance, which the researchers attributed to the small sample size.
Finally, computer-based analyses identified several existing drugs — including fasudil, a medication approved in Japan to treat abnormal narrowing of blood vessels in the brain — as potential modulators of the identified genes, raising the possibility of future drug repurposing.
“In summary, the identified NPRGs-related biomarkers hold diagnostic potential for IPF, with further research needed to clarify their functional roles and assess their viability as therapeutic targets or as consequences of the fibrotic process,” the researchers concluded, noting that “given the small sample size … and the reliance on correlation analysis, the conclusions require further validation through larger-scale functional studies.”
