New Research Uncovers Two Potential Therapeutic Approaches too Combat Fibrosis
Yale researchers have identified two distinct pathways offering promising new avenues for treating fibrotic diseases,conditions where scarring leads to organ and tissue dysfunction. The studies, detailed in recent publications, focus on the roles of epiregulin and the STAT1 protein in driving fibrosis, notably in skin disorders.
The first line of investigation centered on identifying shared mechanisms between scleroderma and graft-versus-host disease, both known to cause fibrosis. By comparing single-cell RNA sequencing data from patients with these conditions, researchers discovered consistently elevated levels of epiregulin – a signaling protein – as a common characteristic. Subsequent testing of an anti-epiregulin antibody in humanized mouse models and patient skin biopsies demonstrated that inhibiting epiregulin reduced biomarkers associated with fibrosis, suggesting its potential as a therapeutic target. Future studies will explore the antibody’s efficacy in other fibrotic diseases like lupus and hidradenitis suppurativa.
A second study aimed to differentiate the biological processes occurring in fibrotic versus non-fibrotic skin diseases. Analyzing single-cell RNA sequencing data from seven inflammatory skin conditions – including atopic dermatitis and psoriasis (non-fibrotic) alongside scleroderma, graft-versus-host disease, and lupus (fibrotic) – revealed heightened activity of the STAT1 protein within fibroblasts, the cells central to the fibrotic process.
Further experiments using mouse models lacking STAT1 demonstrated a meaningful reduction in fibrosis when the EGFR signaling pathway was activated, compared to standard models. Researchers confirmed this finding in vitro using cultured fibroblasts, establishing STAT1 as a crucial component in the progress of fibrosis.
This discovery is particularly relevant given the limitations of current therapies like JAK inhibitors, which target the JAK-STAT pathway. The research indicates that EGFR signaling can activate STAT1 independently of JAKs, possibly explaining why JAK inhibitors are less effective in treating fibrotic conditions. This EGFR-STAT1 pathway therefore represents a novel therapeutic target.
Importantly, the researchers emphasize that the epiregulin/EGFR-STAT1 pathway is not constantly active, but is triggered by specific conditions like injury or inflammation. This suggests that inhibiting these pathways may have a favorable safety profile,as they aren’t essential for normal bodily functions.
“There’s a lot of hope for the future,” stated researcher Robert Flavell, reflecting the optimism surrounding these findings and their potential to improve the lives of patients suffering from fibrotic diseases.
