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  3. Mechanistic insights into targeting APLN/APJ for ameliorating testosterone deficiency and reproductive disorders in diabetic mice

Mechanistic insights into targeting APLN/APJ for ameliorating testosterone deficiency and reproductive disorders in diabetic mice

  • Cell Commun Signal. 2025 Oct 30;23(1):469. doi: 10.1186/s12964-025-02474-8.
Ke Song # 1,  Tao Jing # 2,  Xinyan Yang # 3 4,  Junjun Xia 4,  Zehui Wang 4,  Fang Luo 4,  Chunhua Qiu 5,  Zhaoting Liu 6,  Xiao-Yang Zhao 7 8 9 10 11 12,  Guang Wang 13,  Xianghong Ou 14 15
Affiliations

Affiliations

  • 1 Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong, P. R. China. nanyisk2017@163.com.
  • 2 The Affiliated Guangdong Second provincial General Hospital of Jinan University, Guangzhou, Guangdong, P. R. China.
  • 3 Department of Gynecology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, PR China.
  • 4 State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, P. R. China.
  • 5 Department of Medical Ultrasound, Guangzhou First People's Hospital, Guangzhou, Guangdong, P. R. China.
  • 6 State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, P. R. China. liuzhaoting@i.smu.edu.cn.
  • 7 State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, Guangdong, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 9 Key Laboratory of Mental Health of the Ministry of Education, Guangzhou, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 10 Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangzhou, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 11 Department of Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 12 National Clinical Research Canter for Kidney Disease, Guangzhou, P. R. China. zhaoxiaoyang@smu.edu.cn.
  • 13 Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, P. R. China. wangguang7453@126.com.
  • 14 Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, P. R. China. ouxh@gd2h.org.cn.
  • 15 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China. ouxh@gd2h.org.cn.
  • # Contributed equally.
PMID: 41168800 DOI: 10.1186/s12964-025-02474-8
Abstract

Type 2 diabetes mellitus (T2DM) is frequently associated with testosterone deficiency, which affects male reproductive function. Currently, exogenous testosterone replacement therapy poses inherent risks, underscoring the need to develop safer and more effective treatment strategies. This study aimed to elucidate the mechanism by which ML221, a potent apelin receptor (APJ) functional antagonist, promotes testosterone secretion, and alleviates reproductive dysfunction. Diabetic mouse models demonstrated reduced testosterone levels, impaired spermatogenesis, and low sperm quality. Elevated APLN expression impaired Leydig cell function and testosterone synthesis. Treatment with ML221 restored testosterone levels and spermatogenesis in diabetic mice. Mechanistically, ML221 regulated Leydig cell metabolism by elevating S-D-lactoylglutathione levels, reducing mitochondrial Reactive Oxygen Species, preserving mitochondrial membrane potential, and enhancing adenosine triphosphate production. At the epigenetic level, ML221 enhanced the binding of nuclear receptor subfamily 2 group F member 2 to the promoters of testosterone-synthesizing genes, thereby facilitating testosterone biosynthesis. These findings advance the understanding of the male reproductive system in the context of diabetes and highlight ML221 as a potential therapeutic approach for T2DM-induced testosterone deficiency.

Keywords

APLN/APJ system; Leydig cell; Spermatogenesis; Testosterone deficiency; Type 2 diabetes.

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