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

www.nature.com/emm ARTICLE OPEN 4E-BP1 acts as a molecular rheostat balancing regenerative healing and fibrotic scarring ✉ Hanyu Dou1,2,6, Jianzhou Li1,2,6, Lin Lin1,2, Mengyu Jin1,2, Jingyuan Wang3, Hequn Fu4, Jiongming Lu4, Qinyi Chen5, Leihong Xiang5 , 1,2 ✉ 1,2,5 ✉ Juan Wang and Xiaolei Ding © The Author(s) 2026 1234567890();,: 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 mTORC1/4EBP1 signaling axis during repair. Functional studies revealed that genetic ablation of 4E-BP1, mimicking fully phosphorylated 4EBP1, 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01724-0 INTRODUCTION Skin provides a crucial barrier against environmental insults and possesses a remarkable regenerative capacity. Upon injury, wound healing proceeds through tightly regulated phases: hemostasis, inflammation, proliferation, and remodeling, which coordinately restore tissue integrity and barrier function1,2. This complex process involves clot formation, inflammation, granulation tissue formation, and re-epithelialization, ultimately culminating in scar formation1–3. The quality of healing is influenced by factors including age, metabolic status, and disease burden. When disrupted, these processes can lead to chronic wounds, malignant transformation, or pathological fibrosis4–6. During tissue repair, both resident and recruited cells undergo extensive metabolic rewiring, characterized by enhanced nutrient uptake and utilization, particularly amino acids, glucose, and lipids, which governs regenerative outcomes7–9. This metabolic restructuring provides cellular fuel necessary for energy-intensive regenerative processes, including extensive extracellular matrix (ECM) synthesis, rapid cell proliferation, and coordinated tissue remodeling. Dysregulation of the signaling networks that orchestrate the balance between catabolic breakdown and anabolic reconstruction can severely compromise healing efficiency or precipitate pathological disorders, including the development of chronic non-healing wounds and pathological scars2,10. Despite these critical roles, the molecular mechanisms that integrate nutrient sensing with translational control during skin repair and fibrosis remain incompletely characterized11. Specifically, how translational machinery components regulate mRNA translation to direct wound healing outcomes have been underexplored. The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that functions as a master regulator of cellular growth, metabolism, and tissue homeostasis12,13. mTOR signaling operates through two structurally and functionally distinct complexes, mTORC1 and mTORC2, with mTORC1 acting as a central integrator of nutrient and growth factor cues to drive anabolic metabolism14,15. Previous work from our group and others has demonstrated that precise regulation of mTOR activity is essential for skin morphogenesis16. Genetic disruption of mTORC1 impairs epidermal barrier formation17,18 and delays wound healing, as observed across multiple species, including flies and mice19–21. Clinically, the application of mTORC1 inhibitor rapamycin and its analog leads to disturbed healing responses, emphasizing the contribution of the pathway in tissue repair22. Conversely, hyperactivation of mTORC1, such as through 1 Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China. Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China. 3College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. 4Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 5Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. 6These authors contributed equally: Hanyu Dou, Jianzhou Li. ✉email: fl[email protected]; ; 2 Received: 18 August 2025 Revised: 2 March 2026 Accepted: 3 March 2026 H. Dou et al. 2 loss of upstream negative mediators, such as PTEN or TSC, accelerates wound closure but often promotes tumorigenesis, fibrotic overgrowth, and excessive scarring19,23,24. Together, these findings highlight the need for a finely tuned mTORC1 signaling threshold to support optimal wound healing while preventing pathological fibrosis. A principal effector pathway downstream of mTORC1 governs protein synthesis through the phosphorylation of ribosomal proteins and the eukaryotic translation initiation factor 4Ebinding proteins (4E-BPs)12,25. Among these, 4E-BP1 serves as a key regulator of protein translation initiation via binding to eIF4E, preventing the assembly of the translational initiation complex and thereby repressing translation25,26. Upon mTORC1 activation, 4E-BP1 is phosphorylated and releases eIF4E, thereby licensing selective mRNA translation. Notably, reduced mTOR signaling and the consequent low 4E-BP1 phosphorylation have been observed in diabetic wounds and is associated with impaired healing capacity27–29. Furthermore, emerging evidence implicates the 4E-BP1/eIF4E axis in regulating fibrotic processes30–32. Inhibition of mTORC1/4E-BP1 axis attenuates transforming growth factor-β1 (TGF-β1)-induced fibrotic response in human tenon, lung, and kidney fibroblasts in vitro30–33. Despite these advances, the in vivo function of mTORC1-mediated translational control via 4E-BP1 in skin repair and fibrosis remains insufficiently defined. In this study, we investigated the functional role of 4E-BP1 in skin wound healing and fibrotic remodeling by usi (...truncated)