4E-BP1 acts as a molecular rheostat balancing regenerative healing and fibrotic scarring

Efficient wound healing relies on tightly coordinated protein synthesis to support the complex cellular activities underlying tissue repair. However, the mechanisms governing translational control during tissue regeneration remain incompletely defined. Here, we identify the mTORC1 effector 4E-binding protein 1 (4E-BP1) as a critical regulator of wound repair and fibrotic remodeling. Phosphorylated 4E-BP1 was markedly increased in wounds and fibrotic tissues, indicating dynamic engagement of the mTORC1/4E-BP1 signaling axis during repair. Functional studies revealed that genetic ablation of 4E-BP1, mimicking fully phosphorylated 4E-BP1, enhanced re-epithelialization, angiogenesis, and granulation tissue formation in wound tissues, yet concurrently promoted myofibroblast activation and excessive collagen deposition, and fibrotic progression in bleomycin-induced skin fibrosis. Conversely, sustained overexpression of 4E-BP1 impaired wound closure and attenuated fibrotic responses. Moreover, in vitro, 4E-BP1 expression directly governed transforming growth factor-β1-mediated fibroblast collagen synthesis. Phosphorylated 4E-BP1 levels and related transcriptional signatures were elevated in human skin fibrotic scar tissues. These findings demonstrate that 4E-BP1 acts as an mTORC1-downstream effector that shapes the balance between reparative efficiency and fibrotic remodeling. Targeting the mTORC1/4E-BP1 signaling axis may therefore offer novel therapeutic opportunities to optimize wound healing and prevent pathological scarring.