YTHDF3-mediated m6A Modification Facilitates Osteosarcoma Progression through the FSP1-CoQ10-NAD(P)H Axis to Suppress Ferroptosis
Wei Liu 1,2
Nan Zhu 1,2
Shu Zhang 1,2
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Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, China
Institute of Orthopaedics, Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, China
Emergency Department, Anhui No.2 Provincial People's Hospital, China
These authors had equal contribution to this work
Submission date: 2023-11-10
Final revision date: 2024-03-06
Acceptance date: 2024-04-11
Online publication date: 2024-04-19
Corresponding author
Junfeng Zhan   

Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, China
Osteosarcoma (OS) remains a formidable malignancy, characterized by its relentless nature and limited therapeutic interventions. YTHDF3, a key reader protein recognizing m6A-modified mRNAs, has attracted considerable attention due to its prominent role in cancer biology. This study embarks on an exploration of the intricate interplay between YTHDF3, a vital RNA modification reader protein, m6A RNA modification, and the FSP1-CoQ10-NADPH metabolic pathway in the pathogenesis of OS.

Material and methods:
Firstly, we procured tissue specimens and corresponding non-cancerous tissues from 10 OS patients and cultured OS cell lines. Then, we established a ferroptosis model in OS cells through treatment with RSL3 to reveal the relation between YTHDF3 and ferroptosis.

Clinical evaluation of OS samples revealed a notable upsurge in the expression of YTHDF3 and the concurrent overexpression of ferroptosis-related proteins. In vitro experiments suggested that YTHDF3 potentially facilitated FSP1 mRNA translation through an m6A-dependent mechanism, subsequently inhibiting ferroptosis via the FSP1-CoQ10-NADPH pathway, thereby promoting OS progression.

These compelling findings underscore the promise of targeting the YTHDF3-FSP1 axis as an innovative and potentially transformative therapeutic strategy for the treatment of OS. This study not only enhances our understanding of ferroptosis regulation but also sheds light on the significance of YTHDF3 and FSP1 as potential targets for therapeutic intervention in OS, offering new prospects for cancer treatment strategies.

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