Astragaloside IV inhibits retinal pigment epithelial cell senescence and reduces IL-1β mRNA stability by targeting FTO-mediated m6A methylation

Si-Wei Wang; Ping Li; Shi-Yu Liu; De-Lian Huang; Si-Jia Zhang; Xi-Xi Zeng; Tian Lan; Kai-Li Mao; Yuan Gao; Yi-Fan Cheng; Qing Shen; Ye-Ping Ruan; Zhu-Jun Mao

doi:10.1016/j.phymed.2025.156408

Astragaloside IV inhibits retinal pigment epithelial cell senescence and reduces IL-1β mRNA stability by targeting FTO-mediated m⁶A methylation

Phytomedicine. 2025 Jan 18:138:156408. doi: 10.1016/j.phymed.2025.156408. Online ahead of print.

Authors

Si-Wei Wang¹, Ping Li², Shi-Yu Liu², De-Lian Huang³, Si-Jia Zhang², Xi-Xi Zeng⁴, Tian Lan⁴, Kai-Li Mao⁴, Yuan Gao², Yi-Fan Cheng², Qing Shen⁴, Ye-Ping Ruan⁵, Zhu-Jun Mao⁶

Affiliations

¹ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Panvascular Diseases Research Center, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China. Electronic address: wsw_1972@wmu.edu.cn.
² School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
³ School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁴ Panvascular Diseases Research Center, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
⁵ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: ruanyp@zjtcm.net.
⁶ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China. Electronic address: maozhujun0107@zcmu.edu.cn.

PMID: 39848020
DOI: 10.1016/j.phymed.2025.156408

Abstract

Background: Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of age-related macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified.

Purpose: This study aimed to explore the impacts of Ast on RPE cell senescence and to uncover the molecular mechanisms involved.

Methods: The therapeutic efficacy of Ast was assessed using sodium iodate (NaIO₃)-induced adult retinal pigment epithelial cell line 19 (ARPE-19) cell models and an AMD mouse model. To investigate the mechanisms by which Ast mitigated RPE cell senescence, RNA sequencing (RNA-seq), drug affinity responsive target stability-mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), reverse transcription quantitative PCR (RT-qPCR), as well as western blotting were conducted.

Results: Ast significantly inhibited NaIO₃-treated ARPE-19 cell senescence and protected against NaIO₃-induced AMD in mice. RNA-seq analysis revealed that Ast significantly attenuated inflammation-related signaling pathways and reduced the mRNA levels of interleukin-1 beta (IL-1β). Specifically, Ast decreased the stability of IL-1β mRNA while enhancing its N6-methyladenosine (m⁶A) methylation. Furthermore, Ast directly interacted with fat mass and obesity-associated protein (FTO). Knockdown or pharmacological inhibition of FTO mitigated the senescence and IL-1β expression in NaIO₃-treated ARPE-19 cells. FTO was essential for Ast to inhibit cellular senescence and IL-1β expression. Additionally, inhibition or knockdown of FTO conferred also provided resistance to AMD in the murine model.

Conclusion: Our results indicated that Ast significantly attenuated RPE cell senescence and showed anti-AMD properties. FTO was demonstrated to be a promising therapeutic target for AMD treatment. These findings may provide a deeper understanding of the molecular mechanisms underlying RPE cell senescence in AMD and offer potential strategies for its prevention and management.

Keywords: Astragaloside IV; Cell senescence; FTO; IL-1β; Retinal pigment epithelial cell; m(6)A methylation.