Sfrp2, short for Secreted frizzled-related protein 2, is a vital molecule in the Wnt signaling pathway. It can act as an antagonist of the canonical Wnt signaling pathway and is involved in multiple biological processes, including organ development and disease regulation [6].

In skin, Sfrp2 defines a major fibroblast population with distinct morphology and function compared to other fibroblast populations defined by genes like FMO1. Sfrp2+ fibroblasts are small, elongated, and located between collagen bundles, and differential gene expression suggests their role in matrix deposition [1]. In systemic sclerosis skin, myofibroblasts, which drive fibrosis, arise from an SFRP2hi/DPP4-expressing progenitor fibroblast population [5]. In diabetic cardiomyopathy, Sfrp2 is downregulated in T2DM conditions. Overexpression of Sfrp2 can reverse apoptosis and promote mitochondrial function in an AMPK-PGC1-α-dependent manner, reducing oxidative stress, indicating its potential as a therapeutic biomarker [2]. In melanoma, aged fibroblasts secrete sFRP2, which activates a signaling cascade in melanoma cells, leading to decreased β-catenin, MITF, and APE1, thus driving metastasis and therapy resistance [4]. Pharmacologically blocking SFRP2 in PAI-1-driven SFRP2high cancer-associated fibroblasts can enhance the abscopal effect of radioimmunotherapy [3]. In trophoblast cells, SFRP2 overexpression reduces cell viability, proliferation, and migration by inhibiting the Wnt/β-catenin pathway, suggesting its potential as a therapeutic target for preeclampsia [7]. In diabetic wound healing, suppression of SFRP2 delays the process, affects macrophage infiltration and functional phenotype transition, as well as energy metabolism, while AAV-SFRP2 treatment augments wound healing [8].

In conclusion, Sfrp2 is crucial in various biological processes and disease conditions. Studies, some potentially involving gene knockout or conditional knockout models as inferred from the functional changes observed, have revealed its roles in areas such as skin fibroblast function, fibrosis, cardiomyopathy, cancer metastasis and therapy response, trophoblast cell behavior, and diabetic wound healing. These findings provide valuable insights into disease mechanisms and potential therapeutic targets related to Sfrp2.

References:

1. Tabib, Tracy, Morse, Christina, Wang, Ting, Chen, Wei, Lafyatis, Robert. 2017. SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. In The Journal of investigative dermatology, 138, 802-810. doi:10.1016/j.jid.2017.09.045. https://pubmed.ncbi.nlm.nih.gov/29080679/

2. Ma, Tianyi, Huang, Xiaohui, Zheng, Haoxiao, Hu, Yunzhao, Huang, Yuli. 2021. SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy. In Oxidative medicine and cellular longevity, 2021, 9265016. doi:10.1155/2021/9265016. https://pubmed.ncbi.nlm.nih.gov/34790288/

3. Zhang, Yan-Pei, Guo, Ze-Qin, Cai, Xiao-Ting, Wu, De-Hua, Dong, Zhong-Yi. 2025. PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy. In Cancer cell, , . doi:10.1016/j.ccell.2025.02.024. https://pubmed.ncbi.nlm.nih.gov/40086438/

4. Kaur, Amanpreet, Webster, Marie R, Marchbank, Katie, Ribas, Antoni, Weeraratna, Ashani T. 2016. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. In Nature, 532, 250-4. doi:10.1038/nature17392. https://pubmed.ncbi.nlm.nih.gov/27042933/

5. Tabib, Tracy, Huang, Mengqi, Morse, Nina, Domsic, Robyn, Lafyatis, Robert. 2021. Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin. In Nature communications, 12, 4384. doi:10.1038/s41467-021-24607-6. https://pubmed.ncbi.nlm.nih.gov/34282151/

6. Wu, Yu, Liu, Xinyue, Zheng, Haoxiao, Huang, Xiaohui, Huang, Yuli. 2020. Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease. In International journal of biological sciences, 16, 730-738. doi:10.7150/ijbs.40923. https://pubmed.ncbi.nlm.nih.gov/32071544/

7. Lan, Ruihong, Yu, Yihong, Song, Jie, Xue, Mengdi, Gong, Humin. 2024. SFRP2 suppresses trophoblast cell migration by inhibiting the Wnt/β‑catenin pathway. In Molecular medicine reports, 29, . doi:10.3892/mmr.2024.13190. https://pubmed.ncbi.nlm.nih.gov/38426532/

8. Yang, Jiaqi, Xiong, Guorui, He, Huijuan, Huang, Haili. 2024. SFRP2 modulates functional phenotype transition and energy metabolism of macrophages during diabetic wound healing. In Frontiers in immunology, 15, 1432402. doi:10.3389/fimmu.2024.1432402. https://pubmed.ncbi.nlm.nih.gov/39464880/