Src and β-catenin control a senescence-fibrotic phenotype in uterine fibroid cells

  • Sci Rep. 2026 Jun 26. doi: 10.1038/s41598-026-57742-5.
Md Soriful Islam  1 ,  Valeria I Macri  2 ,  Lauryn Martin  2 ,  Claire Shen  2 ,  Joscelyn Mejias  3 ,  Samya El Sayed  2 ,  Rachel Michel  2 ,  Casie Post  2 ,  Bhuchitra Singh  2 ,  Joshua T Brennan  2 ,  Abigail Fennell  4 ,  Jude M Phillip  4  5  6  7 ,  Mostafa A Borahay  2 ,  Jennifer H Elisseeff  3 ,  James H Segars  2
Affiliations
  • 1. Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, Johns Hopkins Medicine, 720 Rutland Ave, Ross Building, Room 624, Baltimore, MD, 21205, USA. [email protected].
  • 2. Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, Johns Hopkins Medicine, 720 Rutland Ave, Ross Building, Room 624, Baltimore, MD, 21205, USA.
  • 3. Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • 4. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21212, USA.
  • 5. Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, 21212, USA.
  • 6. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21212, USA.
  • 7. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
PMID: 42362678 DOI: 10.1038/s41598-026-57742-5
Abstract

Uterine fibroids (or leiomyomas) are highly prevalent benign tumors in women of reproductive age and are associated with abnormal uterine bleeding, pelvic pain, and infertility. Fibroid tumors are characterized by excessive extracellular matrix deposition and increased tissue stiffness, however the functional impact of this mechanical property in regulating fibroid cell behavior remains poorly understood. Uterine fibroids feature and increased number of senescent cells accompanied by profibrotic and inflammatory signaling but their contribution to fibroid growth is not fully understood. We observed that mechanical stiffness promoted senescence and fibrotic phenotypes in uterine fibroid cells. Fibroid cells cultured on stiff (⁓ 3 GPa) compared to soft (930 kPa) substrates exhibited elevated expression of senescence markers, including p16 and p21, as well as increased levels of fibrosis associated proteins such as fibronectin, PAI1, and α-SMA. Mechanistically, we identified Src and β-catenin as key regulators of this phenotype. Furthermore, the senolytic Src Inhibitor dasatinib reduced senescence and fibrosis markers and attenuated β-catenin activity, suggesting that Src acts upstream of β-catenin in this context. Inhibition of β-catenin using ICG001 or PRI724 suppressed senescence and fibrosis markers and reduced downstream targets including CTGF and cyclin D1. These findings reveal a mechanistic link between mechanical stiffness, cellular senescence, and fibrosis in uterine fibroids, and identify Src and β-catenin as potential therapeutic targets.

Keywords
Dasatinib; Fibrosis; Senescence; Senolytics; Substrate stiffness; Uterine fibroids; β-Catenin.
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