Shenqi Qiangjing Granules Ameliorate Asthenozoospermia in Mice by Regulating Ferroptosis through the METTL3/GPX4 Signaling Axis

Shenqi Qiangjing Granules Ameliorate Asthenozoospermia in Mice by Regulating Ferroptosis through the METTL3/GPX4 Signaling Axis

Qiuyu Lu,¹ Jiabao Ma,² Luying Wei,² Jing Fu,² Xiaoxia Li,² Kedao Lai,³ Xin Li,⁴ Bingyu Xia,⁴ Bin Bin² and Aicun Tang²

¹Deptartment of Pharmacy, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
²The First Affiliated Hospital of Guangxi Traditional Chinese Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
³Guangxi Institute of Chinese Medicine and Pharmaceutical Science, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
⁴Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, P.R. China

Asthenozoospermia is a leading cause of male infertility, yet current pharmacotherapies yield suboptimal outcomes, underscoring the urgent need for novel treatment modalities. Herein, we induced asthenozoospermic mouse models using busulfan and investigated the therapeutic effects of Shenqi Qiangjing Granules (SQ) on testicular pathology, serum sex hormone and steroidogenic enzyme levels, and ferroptosis. Furthermore, utilizing GC-1 spg cell lines, we elucidated the role of the METTL3-mediated m⁶A modification in GPX4 mRNA stability. Treatment with SQ or Fer-1 (an inhibitor of ferroptosis) significantly ameliorated testicular pathological injury, restored abnormal serum sex hormone levels, and enhanced testicular steroidogenic enzyme expression, highlighting the therapeutic potential of targeting ferroptosis in asthenozoospermia. In elucidating the molecular mechanism of METTL3 in ferroptosis, we found that METTL3 regulates GPX4 mRNA stability, subsequently impacting ferroptosis and sperm quality. Knockdown of METTL3 mimicked the effects of SQ treatment, while overexpression of METTL3 partially reversed SQ-mediated effects on ferroptosis and asthenozoospermia, underscoring the pivotal role of METTL3 in SQ therapy. In conclusion, the METTL3-GPX4-ferroptosis axis emerges as a novel regulatory pathway in the pathogenesis of asthenozoospermia. Targeting this axis, particularly through interventions such as SQ treatment, holds promise for the management of male infertility.

Key words —— male infertility; METTL3-GPX4-ferroptosis axis; traditional Chinese medicine

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Tohoku J. Exp. Med., 2024 September, 264(1), 9-19.

*These authors contributed equally to this work.

Correspondence: Aicun Tang, The First Affiliated Hospital of Guangxi Traditional Chinese Medical University, No.89-9, Dongge Road, Nanning, Guangxi Zhuang Autonomous Region 530023, P.R. China.

e-mail: lqyyxb@126.com

Bin Bin, The First Affiliated Hospital of Guangxi Traditional Chinese Medical University, No.89-9, Dongge Road, Nanning, Guangxi Zhuang Autonomous Region 530023, P.R. China.

e-mail: 2967203832@qq.com