FTO-mediated the destabilization of RASGRF1 mRNA impedes thyroid cancer progression and suppresses macrophage M2 polarization

Sep 24, 2026

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Background RASGRF1 functions as a guanine nucleotide exchange factor across cancers, including thyroid cancer (THCA). This work defines how RASGRF1 drives THCA progression and clarifies an m6A-dependent mechanism that governs RASGRF1 dysregulation. Methods include immunoblotting, immunohistochemistry, quantitative PCR, and functional assessment via colony formation, EdU, apoptosis/flow cytometry, transwell assays, and xenograft experiments. Results show RASGRF1 upregulation in THCA and that its depletion slows growth, invasion, and ferroptosis control in vitro while reducing tumor growth in vivo. Mechanistically, FTO destabilizes RASGRF1 mRNA through m6A-dependent regulation, suppressing macrophage M2 polarization and THCA malignant progression. Conclusion FTO-mediated RASGRF1 mRNA instability diminishes THCA progression and macrophage M2 polarization, supporting anti-RASGRF1 strategies for THCA treatment.

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CategoryHealthcare

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Cell Biol Toxicol (2025) 41:123 [https://doi.org/10.1007/s10565-025-10073-z](https://doi.org/10.1007/s10565-025-10073-z) FTO‑mediated the destabilization of RASGRF1 mRNA impedes thyroid cancer progression and suppresses macrophage M2 polarization Zongyu Li · Jiancang Ma · Hao Guan · Jingyue Lai · Fangshi Xu · Gang Cao Received: 1 April 2025 / Accepted: 18 July 2025 © The Author(s) 2025 Abstract Background The guanine nucleotide exchange factor RASGRF1 actively acts in a broad range of human cancers, including thyroid cancer (THCA) . This study defined the activity of RASGRF1 in THCA progression and elucidated the m6A modification mechanism governing dysregulation of RASGRF1 . Methods Expression analyses were performed by immunoblotting, immunohistochemistry (IHC) or quantitative PCR. Cell growth was evaluated by colony formation and EdU proliferation assays. Animal | Highlights
(1) RASGRF1 depletion promotes THCA cell ferroptosis.
(2) RASGRF1 depletion reduces macrophage M2 polarization.
(3) FTO reduces RASGRF1 mRNA stability via an m6Adependent mechanism.
(4) FTO-mediated the instability of RASGRF1 mRNA diminishes THCA progression. | | --- | | Supplementary Information The online version contains supplementary material available at [https://doi](https://doi). org/10.1007/s10565-025-10073-z. | Z. Li · J. Ma · H. Guan · J. Lai · F. Xu Department of Vascular Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi, China G. Cao (*) Department of Thyroid Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, No 157 Xiwu Road, Xi’an 710004, Shaanxi, China e-mail: [15029997871@163.com](15029997871@163.com) experiments tested the function of RASGRF1 in xenograft growth. The conditioned medium (CM) of THCA cells was used to treat THP-1-differentiated macrophages. Cell apoptosis and CD206+ macrophages were assessed by flow cytometry. Cell invasiveness and migratory ability were detected by transwell assays. The influence of FTO in RASGRF1 was evaluated by RNA immunoprecipitation (RIP) and MeRIP assays. Results RASGRF1 was upregulated in human THCA. RASGRF1 depletion retarded THCA cell growth, motility, invasiveness and promoted cell apoptosis and ferroptosis in vitro, as well as diminished the growth of TPC1 THCA xenograft tumorsin vivo. Moreover, RASGRF1 depletion diminished M2 polarization and migration of THP-1-differentiated macrophages. Mechanistically, FTO reduced RASGRF1 mRNA stability via an m6A-dependent mechanism. FTO upregulation suppressed THCA malignant behaviors, promoted cell ferroptosis and reduced macrophage M2 polarization and migration through repression of RASGRF1 . Conclusion Our findings suggest that FTO-mediated the instability of RASGRF1 mRNA diminishes THCA-related macrophage M2 polarization and THCA progression. Anti-RASGRF1 strategies maybe useful for the treatment of THCA. Keywords Thyroid cancer · Ferroptosis · Macrophage M2 polarization · RASGRF1 · M6A modification Introduction As the most prevalent endocrine malignancy, thyroid cancer (THCA) is rapidly increasing in incidence worldwide. THCA has a broad range of clinical manifestations, ranging from low-mortality tumors inmost cases to awfully aggressive malignancies, such as anaplastic THCA (Chen et al. 2023 ; Boucai et al. 2024) . Although the standard therapies can effectively control well-differentiated THCA, these treatments are limited to cure medullary and anaplastic THCA (Nabhan et al. 2021 ; Maniakas et al. 2022) . Uncovering the molecular determinants responsible for thyroid carcinogenesis may contribute to the development of innovatory targeted therapies. Ferroptosis, a unique modality of cell death, has been implicated in THCA development (Lin et al. 2021) . Pharmacological modulation of ferroptosis has been proposed to have great potential for cancer treatment (Jiang et al. 2021). As a result, more research is being done to uncover the molec

FAQs

What role does RASGRF1 play in thyroid cancer progression?

RASGRF1 is upregulated in human THCA and its depletion retards THCA cell growth, motility, invasiveness, and promotes apoptosis and ferroptosis. It also diminishes the growth of THCA xenograft tumors in vivo.

How does FTO influence RASGRF1 in this study?

FTO reduces RASGRF1 mRNA stability via an m6A-dependent mechanism. FTO upregulation suppresses THCA malignant behaviors and reduces macrophage M2 polarization through repression of RASGRF1.

Why is macrophage M2 polarization important for THCA in this research?

The study links THCA progression with macrophage M2 polarization. RASGRF1 depletion reduces M2 polarization and migration of differentiated THP-1 macrophages, and FTO-mediated effects further suppress these pro-tumorigenic phenotypes.

Sep 24, 2026

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