Astragaloside IV inhibits retinal pigment epithelial cell senescence and reduces IL-1β mRNA stability by targeting FTO-mediated m6A methylation
- Phytomedicine. 2025 Mar:138:156408. doi: 10.1016/j.phymed.2025.156408.
- 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: [email protected].
- 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: [email protected].
- 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: [email protected].
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.