Engrailed-1: a context-dependent regulator of development, fibroblast plasticity, fibrosis, and cancer
Year: 2026
Type: article
Abstract: Background The homeodomain transcription factor Engrailed-1 (EN1) is best known for its roles in developmental patterning and the maintenance of neuronal integrity. Recent studies indicate that EN1 can be reactivated under pathological stress, where it contributes to fibroblast state transitions, fibrotic remodeling, and selected cancer phenotypes. In this review, we integrate the diverse biological roles of EN1 across embryonic development, tissue regeneration, fibrosis, and oncogenesis. We distinguish correlative expression patterns from causal evidence and incorporate recent insights from single-cell and spatial transcriptomic studies. Main Findings In the skin, fibroblasts with an EN1 lineage history have a strong propensity for scar formation. Injury-associated mechanical tension can also induce EN1 expression in previously EN1-negative fibroblasts through a YAP-dependent mechanism. TGF-β/SMAD3 signaling provides an additional route to EN1 induction and links EN1 to cytoskeletal remodeling, ROCK activity, and myofibroblast differentiation. Studies using targeted siRNA delivery indicate that this profibrotic program is at least partly reversible. In cancer, the strongest functional evidence for EN1 involvement comes from basal-like breast cancer, pancreatic ductal adenocarcinoma, glioma, and adenoid cystic carcinoma, although the downstream consequences are highly dependent on cellular context. Conclusion EN1 is better viewed as a context-dependent regulator of cell state than as a universal oncogene or a generic fibrosis marker. Therapeutic targeting of EN1 will therefore require cell-specific delivery, well-defined direct regulatory networks, and careful assessment of on-target adverse effects.
Authors: Liang Ning, Kejun Zhang
Institution: Affiliated Hospital of Qingdao University
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225321950