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FRZB-induced anti-angiogenic effect via Caveolin-1-mediated TGFβ signalling
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  • Published: 07 April 2026

FRZB-induced anti-angiogenic effect via Caveolin-1-mediated TGFβ signalling

  • Ching-Jou Chen1 na1,
  • Lei Zhou2,3 na1,
  • Han-Tang Chen1,4,
  • Veluchamy Amutha Barathi1,4,5,
  • Beiying Qiu1,4,
  • Asfa Alli-Shaik6,
  • Rui Ning Chia1,4,
  • Seok Ting Lim1,4,
  • Chaemin Joo1,4,
  • Ning Cheung1,7,
  • Choi Mun Chan7,
  • Siew Kwan Koh4,
  • Alison Tan1,4,
  • Ravi Kumar Verma8,
  • Hao Fan  ORCID: orcid.org/0000-0003-0199-97528,9,
  • Weihua Song1,
  • David Virshup  ORCID: orcid.org/0000-0001-6976-850X1,
  • Jayantha Gunaratne  ORCID: orcid.org/0000-0002-5377-65376,10,
  • Tien Yin Wong  ORCID: orcid.org/0000-0002-8448-12641,7,11,
  • Gemmy Chui Ming Cheung1,4,7,
  • Wanjin Hong  ORCID: orcid.org/0000-0002-1719-89606 &
  • …
  • Xiaomeng Wang  ORCID: orcid.org/0000-0002-1036-27641,4,6 

Nature Communications , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Macular degeneration
  • Recombinant protein therapy
  • Target identification
  • Target validation

Abstract

Pathological neovascularization and vascular leakage are central drivers of many sight-threatening diseases. While strategies targeting vascular endothelial growth factor (VEGF) have improved clinical outcomes, many patients do not benefit from the treatment, highlighting the need for alternative therapeutic strategies. Two independent vitreous proteomics studies in patients with proliferative diabetic retinopathy (PDR) reveal a significant reduction in Frizzled-related Protein (FRZB), a finding recapitulated in preclinical models of ocular angiogenesis. Here, we show that loss of Frzb exacerbates ocular angiogenesis, whereas therapeutic delivery of Fc-recombinant FRZB or its netrin-related motif (NTR) robustly suppresses and reverses ocular angiogenesis across various preclinical models. Fc-NTR acts additively with Aflibercept, supporting its potential as a combination therapy. Mechanistically, FRZB binds Caveolin-1 (CAV1), inhibits its phosphorylation at Tyr42, promotes retention of the TGFβ receptor ALK5, and enhances Smad2/3 signalling. These findings define FRZB as a potent suppressor of ocular angiogenesis and establish a promising therapeutic avenue.

Data availability

Source data with specific p values for all figures are provided with this paper. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD036033, PXD073342 and PXD073005. Additional details on datasets and protocols that support the findings of this study will be made available by the corresponding author upon request. Source data are provided with this paper.

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Acknowledgements

This work was supported by a Start-Up grant to X.W. at Duke-NUS Medical School; BMRC-SIPRAD grant to X.W., G.C., W.H., and T.W.; NMRC – LCG Grant (Grant No. OFLCG23may-0032) for the Translational Asian Age-related macular degeneration Programme (TAAP) to X.W. and G.C., and Support from the InnoHK initiative and the Hong Kong Special Administrative Region Government to L.Z. NTU PPP platform for recombinant protein production.

Author information

Author notes

  1. These authors contributed equally: Ching-Jou Chen, Lei Zhou.

Authors and Affiliations

  1. Duke-NUS Medical School, Singapore, Singapore

    Ching-Jou Chen, Han-Tang Chen, Veluchamy Amutha Barathi, Beiying Qiu, Rui Ning Chia, Seok Ting Lim, Chaemin Joo, Ning Cheung, Alison Tan, Weihua Song, David Virshup, Tien Yin Wong, Gemmy Chui Ming Cheung & Xiaomeng Wang

  2. Department of Applied Biology and Chemical Technology, School of Optometry, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hung Hom, Hong Kong

    Lei Zhou

  3. Centre for Eye and Vision Research (CEVR), Shatin, Hong Kong

    Lei Zhou

  4. Singapore Eye Research Institute, The Academia, Singapore, Singapore

    Han-Tang Chen, Veluchamy Amutha Barathi, Beiying Qiu, Rui Ning Chia, Seok Ting Lim, Chaemin Joo, Siew Kwan Koh, Alison Tan, Gemmy Chui Ming Cheung & Xiaomeng Wang

  5. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Veluchamy Amutha Barathi

  6. Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Asfa Alli-Shaik, Jayantha Gunaratne, Wanjin Hong & Xiaomeng Wang

  7. Singapore National Eye Centre, Singapore, Singapore

    Ning Cheung, Choi Mun Chan, Tien Yin Wong & Gemmy Chui Ming Cheung

  8. Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Ravi Kumar Verma & Hao Fan

  9. Institute for Molecular and Cellular Therapeutics, Chinese Institutes for Medical Research, Beijing, China

    Hao Fan

  10. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Jayantha Gunaratne

  11. Beijing Visual Science and Translational Eye Research Institute (BERI), Tsinghua Medicine, Medical Sciences Building, Tsinghua University, Beijing, China

    Tien Yin Wong

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  21. Wanjin Hong
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  22. Xiaomeng Wang
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Contributions

X.W. conceived and designed the study. X.W., C.J.C., H.T.C., V.A.B., B.Q., R.N.C., S.T.L., C.J., W.S. and A.T. performed in vitro, ex vivo, and in vivo angiogenesis assays and analyzed the data. L.Z., J.G., A.A.-S. and S.K.K. performed proteomics analyses. C.J.C., H.T.C., B.Q., R.N.C. and S.T.L. carried out molecular biology and biochemistry studies. R.K.V. and H.F. modeled the FRZB and CAV1 interaction. N.C. and C.M.C. helped with clinical evaluation and patient sample collection. T.Y.W. and G.C.C.M. provided critical clinical insights and guided the clinical study design. X.W., C.J.C., H.T.C., L.Z., J.G., R.K.V., W.S. and H.F. drafted the manuscript. D.V., T.Y.W., G.C.C.M. and W.H. reviewed, revised, and provided critical comments on the manuscript.

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Correspondence to Xiaomeng Wang.

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Chen, CJ., Zhou, L., Chen, HT. et al. FRZB-induced anti-angiogenic effect via Caveolin-1-mediated TGFβ signalling. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71326-x

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  • Received: 01 September 2025

  • Accepted: 17 March 2026

  • Published: 07 April 2026

  • DOI: https://doi.org/10.1038/s41467-026-71326-x

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