Illustration depicting healthy lungs embracing lungs damaged by cystic fibrosis, symbolizing the potential therapeutic effect of SPLUNC1.

Breathe Easier: New Hope for Cystic Fibrosis with SPLUNC1 Peptide

Elliot Brynn in Health & Wellness December 2025 • 4 min read.

"Could a peptide derived from a naturally occurring protein offer a breakthrough in treating the underlying causes of cystic fibrosis?"

Cystic fibrosis (CF) is a genetic disorder that primarily affects the lungs, leading to chronic infections and breathing difficulties. This occurs due to mutations in the CFTR gene, which disrupts the balance of fluid and salt transport in the airways.

One of the major consequences of CF is the buildup of thick mucus in the lungs. This is primarily caused by the loss of normal mucociliary clearance that results in chronic bacterial infections. Inflammation and progressive lung destruction further exacerbate this condition, eventually leading to lung failure.

A promising new approach focuses on attenuating the epithelial sodium channel (ENaC). Recent research explores the potential of a peptide derived from SPLUNC1, a naturally occurring protein, to regulate ENaC activity and alleviate CF-related lung issues.

Understanding the ENaC Connection and SPLUNC1's Role

Illustration depicting healthy lungs embracing lungs damaged by cystic fibrosis, symbolizing the potential therapeutic effect of SPLUNC1.

The epithelial sodium channel (ENaC) plays a crucial role in regulating the amount of fluid on the surface of the lungs. In CF, the hyperactivity of ENaC leads to excessive sodium absorption, causing dehydration of the mucus and further impairing mucociliary clearance. This creates an environment ripe for bacterial infections and chronic inflammation.

Researchers have been investigating ways to inhibit ENaC activity to restore the balance of fluid in the airways. SPLUNC1, a secreted protein naturally found in the lungs, has shown promise in this area. SPLUNC1 regulates ASL by protecting ENaC from proteolytic cleavage, preventing ENaC activation.

SPLUNC1 and ENaC: SPLUNC1 protects ENaC, therefore preventing activation.
pH Sensitivity: SPLUNC1's effectiveness is impacted by pH levels. SPLUNC1 inhibitory domain was not able to bind to ENaC at an acidic pH as would be found in the ASL of CF airways.
S18 Peptide: Researchers have identified an 18-amino acid sequence (S18) within SPLUNC1 that directly inhibits ENaC, regardless of pH levels.

To test the S18 peptide's potential, researchers conducted a series of experiments using human bronchial epithelial cells lacking CFTR. The results showed that the S18 peptide was able to penetrate the thick mucus layer characteristic of CF lungs and effectively reduce ASL absorption. Importantly, it achieved this without causing the kidney-related side effects associated with traditional ENaC inhibitors like amiloride.

Future Directions and Hope for CF Patients

The research on the SPLUNC1-derived peptide S18 offers a promising new avenue for treating cystic fibrosis. Unlike some existing therapies, S18 targets the underlying mechanisms of the disease, addressing the fluid imbalance and mucus buildup that lead to chronic infections and lung damage.

Clinical trials are already underway to evaluate the safety and efficacy of SPX-101, an inhaled solution containing the S18 peptide, in adult CF patients. These trials represent a significant step forward in translating this research into a potential new treatment option.

While further research is needed, the findings suggest that S18 could be a valuable addition to the arsenal of CF therapies, potentially improving lung function and quality of life for individuals living with this challenging condition. This highlights the importance of personalized medicine and combination therapies for effectively managing CF lung disease, ensuring a better future for patients.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1152/ajplung.00516.2017, Alternate LINK

Title: Therapeutic Attenuation Of The Epithelial Sodium Channel With A Splunc1-Derived Peptide In Airway Diseases

Subject: Cell Biology

Journal: American Journal of Physiology-Lung Cellular and Molecular Physiology

Publisher: American Physiological Society

Authors: James F Collawn, Rafal Bartoszewski, Ahmad Lazrak, Sadis Matalon

Published: 2018-01-04

Everything You Need To Know

What is Cystic Fibrosis and how does it affect the lungs?

Cystic Fibrosis (CF) is a genetic disorder primarily affecting the lungs. It is caused by mutations in the CFTR gene, which disrupts the normal balance of fluid and salt transport in the airways. This leads to the buildup of thick mucus, chronic infections, inflammation, and breathing difficulties. Ultimately, CF can lead to lung failure. The focus of the research is to address these underlying issues to alleviate the disease's impact.

What is the role of the epithelial sodium channel (ENaC) in the context of Cystic Fibrosis?

The epithelial sodium channel (ENaC) is a protein that regulates the amount of fluid on the surface of the lungs. In individuals with CF, ENaC becomes overactive, leading to excessive sodium absorption. This causes the airway surface liquid (ASL) to dehydrate. This dehydration impairs mucociliary clearance, the process of clearing mucus from the airways, making it easier for bacteria to thrive, leading to chronic infections and inflammation. Targeting ENaC activity, therefore, is a key strategy in addressing the core problems of CF.

How does the SPLUNC1 protein relate to the treatment of Cystic Fibrosis?

SPLUNC1 is a naturally occurring protein found in the lungs. It plays a role in regulating the ASL. Research has shown that SPLUNC1 protects ENaC from being activated, thus helping to maintain the appropriate balance of fluid in the airways. In the context of CF, where ENaC is overactive, SPLUNC1's function is particularly relevant because it can help counteract this hyperactivity, potentially improving the ASL balance and reducing mucus buildup.

What is the S18 peptide, and how is it being used to treat Cystic Fibrosis?

The S18 peptide is an 18-amino acid sequence derived from the SPLUNC1 protein. Researchers have identified this sequence as having the ability to directly inhibit ENaC, regardless of pH levels. Experiments showed that the S18 peptide could penetrate the thick mucus layer characteristic of CF lungs. It effectively reduces ASL absorption without causing the kidney-related side effects associated with traditional ENaC inhibitors like amiloride. This makes S18 a promising candidate for treating CF.

Why is the research on the S18 peptide significant for Cystic Fibrosis patients?

The implications of this research are significant because the S18 peptide offers a new approach to treating CF by targeting the underlying mechanisms of the disease. It aims to restore the fluid balance in the airways and reduce mucus buildup. By addressing these fundamental issues, the S18 peptide has the potential to reduce chronic infections, inflammation, and lung damage associated with CF. Furthermore, it offers a targeted treatment that may avoid the side effects of other drugs.