Targeting cell death pathway may offer new strategy for treating IPF

Problems in a cell death process called ferroptosis may contribute to the formation of scar tissue in the lungs in idiopathic pulmonary fibrosis (IPF), a study suggests.

In ferroptosis, which is an iron-dependent process, reactive oxygen molecules damage cell membranes, leading to cell death. In the study, the researchers described a molecular pathway by which IPF decreases ferroptosis in scar-forming cells of the lungs.

“Collectively, these results elucidate a novel pathway of disease progression in IPF that could potentially be targeted for the diagnosis or intervention,” they wrote. The study, “LRP1 activated by AT2 cell-secreted MDK inhibits fibrotic ferroptosis in idiopathic pulmonary fibrosis,” was published in iScience.

In pulmonary fibrosis (PF), a buildup of scar tissue in the lungs leads to symptoms, such as shortness of breath, and a dry, hacking cough. IPF is a type of PF without a clear underlying cause.

Recommended Reading

June 24, 2026 News by Michela Luciano, PhD

Promising oral IPF treatment earns FDA orphan drug designation

Interaction between AT2 and CTHRC1+ cells

Research has suggested that, in IPF lungs, alveolar type 2 (AT2) cells, which play a role in lung repair and regeneration, become abnormal. These dysfunctional AT2 cells tend to accumulate near collagen triple helix repeat-containing 1-positive (CTHRC1+) fibroblasts, that is, types of cells that generate scar tissue. The precise relationships between AT2 and CTHRC1+ cells in disease conditions remain unclear, however.

“Our study investigated the aberrant intercellular communication underlying this process,” wrote the researchers, who first confirmed the clustering of AT2 cells and CTHRC1+ fibroblasts in samples of lung tissue from humans with IPF and a mouse model of the disease. Compared to healthy tissue samples, there were more CTHRC1+ fibroblasts in disease conditions.

A combination of genetic analysis and cellular experiments suggested that ferroptosis in CTHRC1+ fibroblasts decreased in IPF compared with healthy conditions. Reducing cell death could explain the accumulation of CTHRC1+ fibroblasts. “Therefore, we suggest that AT2 cells closely interact with CTHRC1+ fibroblasts and that their reciprocal relationship may be a key factor contributing to the progression of IPF,” the researchers wrote.

They next examined patterns in a preexisting dataset of genetic activity in IPF AT2 cells and found an increase in genes associated with the midkine (MDK) protein, which plays important roles in cell survival and growth.

These rising MDK levels were reflected in the blood of people with IPF, potentially serving as a biological marker of disease activity. Also, the team found a correlation between MDK levels and the degree of respiratory dysfunction in patients.

“The robust association between [blood] plasma MDK and functional impairment supports the translational relevance of MDK as a biomarker that reflects ongoing disease activity, potentially from relatively early phases,” the researchers wrote.

While this could be useful diagnostically, it doesn’t explain how high MDK in AT2 cells affected CTHRC1+ fibroblasts. To assess this, they grew samples of AT2 cells alongside fibroblasts. The results suggested MDK bound to proteins called low-density lipoprotein receptor-related protein 1 (LRP1) on the surface of fibroblasts.

Genetic modifications to eliminate MDK or LRP1 led to an increase in ferroptosis. Conversely, boosting levels of MDK or LRP1 further suppressed ferroptosis. This demonstrates a mechanism linking high MDK in AT2 cells to excessive fibroblast growth in IPF.

Using CTHRC1+ fibroblasts, the researchers examined how exposure to MDK affected proteins within the cells, and found that MDK binding to LRP1 increased levels of otubain1 (OTUB1), a protein that regulates other proteins through a process known as deubiquitination. In CTHRC1+ fibroblasts, OTUB1 deubiquitinated a protein called SLC7A11, increasing its activity.

Contributing to scar formation

In prior research, it’s been shown that SLC7A11 plays important roles in regulating ferroptosis. Gene engineering experiments in mice with IPF-like traits showed that increasing OTUB1 levels increased SLC7A11, exacerbating IPF processes. Conversely, decreasing SLC7A11 partially reversed pulmonary fibrosis.

“To our knowledge, the present study is the first to demonstrate that OTUB1/ SLC7A11 affects fibroblast ferroptosis in IPF, leading to disease progression and deterioration,” the researchers wrote.

Taken together, these experiments delineate a molecular pathway that could contribute to scar formation in IPF. In the disease state, AT2 cells release MDK, which activates LRP1 on CTHRC1+ fibroblasts. This, in turn, increases OTUB1 levels, stabilizes SLC7A11 and reduces ferroptosis. Without ferroptosis to regulate fibroblast levels, the fibroblasts accumulate, creating scar tissue.

The researchers said the use of a mouse model of IPF that may not fully capture the progressive nature of the disease, plus the low availability of human IPF tissue samples were limitations in their study. “Future studies with larger [human] cohorts will be important to confirm the clinical robustness of this pathway,” they wrote.

If experiments continue to support this regulatory signaling pathway, it may provide avenues for targeting disease processes in IPF. “The consistent evidence from integrated bioinformatics, cellular assays, and animal models strongly supports our central conclusion that targeting this axis could be a viable therapeutic strategy for IPF,” they wrote.