Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

Teranishi, R.; Itami, T.; Sasaki, M.; Kennedy, K. V.; Zhou, Y.; Umeweni, C.; McMillan, E.; Anandakrishnan, A.; Lee, R.; Dhakal, D.; Golden, H.; Davis, G.; Karakasheva, T.; Mahon, M.; Peterson, B.; Winters, H.; Pollack, J.; Vinit, N.; Wilkins, B.; Manfredi, M.; Hamilton, T.; Dao, D.; Whelan, K. A.; Wechsler, J.; Spinner, N.; Partridge, E.; Muir, A.

doi:10.64898/2026.01.27.702012

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bioRxiv · 10.64898/2026.01.27.702012

Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

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Abstract

Background & AimsUnchecked inflammation in Eosinophilic esophagitis (EoE) leads to esophageal fibrosis and eventual stricture. Differentiated fibroblasts, termed myofibroblasts, are the main effector cells in fibrosis, responsible for secreting extracellular matrix proteins leading to tissue stiffness. Regulating myofibroblasts has not been explored as a therapeutic possibility in the fibrostenotic esophagus. Herein, we aim to investigate the efficacy of Prostaglandin E2 (PGE2) in dedifferentiation of the EoE myofibroblast. MethodsWe evaluated the efficacy and mechanism of myofibroblast dedifferentiation using fetal esophageal fibroblasts (FEF3), patient-derived fibroblasts, and a murine model of EoE. ResultsFibrosis markers (SMA, FN1, and COL1A1) and contractility of myofibroblasts were significantly decreased by PGE2 via the cAMP pathway. PGE2 treatment decreased nuclear accumulation of phospho-Smad2/3-YAP complex and induced phospho-YAP proteasomal degradation. Transcriptome analyses of FEF3 treated with TGF{beta} or PGE2 revealed that the Integrin1 pathway, and specifically thrombospondin 1 (THBS-1), was significantly upregulated by TGF{beta} and downregulated by PGE2, as supported by pseudo-bulk single-cell RNA-seq of EoE biopsies. THBS-1 was shown to be regulated by PGE2 via the cAMP/YAP pathway, and its knockdown induced myofibroblasts dedifferentiation. In a murine model of EoE, Butaprost, agonist of the E-prostanoid G protein-coupled receptor 2, treatment significantly reduced the expression of THBS-1, SMA, and FN1 along with a decrease in YAP nuclear translocation. Additionally, collagen fiber organization in the lamina propria was markedly reduced. ConclusionPGE2 promotes dedifferentiation of myofibroblasts in EoE via the cAMP/YAP/ THBS-1 pathway. Our data suggest that PGE2 is a promising treatment strategy for EoE with stenosis. What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSIn Eosinophilic esophagitis, unchecked inflammation and tissue stiffness drives fibroblast differentiation and fibrostenosis of the esophagus, yet targeting myofibroblasts as regulators of extracellular matrix deposition in fibrostenotic disease remains clinically unexplored. New FindingsProstaglandin E2 promotes dedifferentiation of myofibroblasts in eosinophilic esophagitis via the cAMP/YAP pathway, with Thrombospondin-1 identified as a critical YAP regulated target driving fibrostenosis. LimitationsThis study focused on fibroblast-specific mechanisms. The effects of PGE2 on esophageal epithelial differentiation, barrier function, and immune cell recruitment in EoE remain to be determined. Clinical Research RelevanceThis study demonstrates proof-of-concept that pharmacological reversal of established fibrosis is achievable in EoE. PGE2 and its EP2-selective agonists represent translatable therapeutic targets for fibrostenotic EoE--a patient population that remains treatment-refractory to current immunosuppressive approaches. Basic Research RelevanceThe cAMP/YAP/THBS-1 signaling in fibroblasts emerges as a critical therapeutic target for esophageal fibrosis. Importantly, this work demonstrates that terminally differentiated myofibroblasts retain remarkable plasticity and can dedifferentiate--challenging the paradigm that fibrosis is irreversible.

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Teranishi, R., Itami, T., Sasaki, M., Kennedy, K. V., Zhou, Y., Umeweni, C., McMillan, E., Anandakrishnan, A., Lee, R., Dhakal, D., Golden, H., Davis, G., Karakasheva, T., Mahon, M., Peterson, B., Winters, H., Pollack, J., Vinit, N., Wilkins, B., Manfredi, M., Hamilton, T., Dao, D., Whelan, K. A., Wechsler, J., Spinner, N., Partridge, E., Muir, A.. 2026-01-29. Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis. https://doi.org/10.64898/2026.01.27.702012

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