PRDX1 promotes testosterone synthesis and attenuates aging via redox regulation of ATG4B to modulate lipophagy

Hanbin Zhang, Ke Ma, Yuge Zhuang, Xixian Cen, Xiaoyuan Zhang, Shipeng Ruan, Hongrui Feng, Runduan Yi, Zicong Huang, Chuyu Huang, Minyu Xie, Lan Tang, Xiong Cao, Guofei Zhang (), Xiangjin Kang (), Yong Fan () and Zhenguo Chen ()
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Hanbin Zhang: Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital of Guangzhou Medical University, Department of Obstetrics and Gynecology
Ke Ma: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Yuge Zhuang: Southern Medical University, Department of Urology, The Seventh Affiliated Hospital
Xixian Cen: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Xiaoyuan Zhang: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Shipeng Ruan: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Hongrui Feng: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Runduan Yi: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Zicong Huang: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences
Chuyu Huang: Southern Medical University, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital
Minyu Xie: Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital of Guangzhou Medical University, Department of Obstetrics and Gynecology
Lan Tang: Southern Medical University, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences
Xiong Cao: Southern Medical University, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences
Guofei Zhang: Southern Medical University, Department of Urology, The Seventh Affiliated Hospital
Xiangjin Kang: Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital of Guangzhou Medical University, Department of Obstetrics and Gynecology
Yong Fan: Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital of Guangzhou Medical University, Department of Obstetrics and Gynecology
Zhenguo Chen: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Cell Biology, School of Basic Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Testosterone insufficiency disrupts spermatogenesis and expedites male aging. Autophagy facilitates testosterone synthesis. However, a molecular reduction mechanism of autophagy-related protein 4 homolog B (ATG4B) has not been established. Herein, we reveal that peroxiredoxin 1 (PRDX1) is clinically associated with male fertility disorders. Adult mutant mice with Leydig cell (LC)-specific deletion of the Prdx1 gene exhibit premature testicular aging and infertility. A series of in vivo and in vitro experiments, in combination with multi-omics analyses, demonstrate that PRDX1 inactivation impairs lipophagy and testosterone synthesis in LCs. Mechanistically, Cys52 and Cys173 in PRDX1 specifically target the redox-site Cys78 in ATG4B to preserve the delipidating activity of Cys74 in ATG4B, thereby promoting autophagic flux. Furthermore, PRDX1 dysfunction exacerbates testicular and systematic aging in aged mice, which can be alleviated by a 2-cysteine mimic, ebselen. Collectively, our findings demonstrate that PRDX1 promotes lipophagy and testosterone synthesis by regulating ATG4B. Our findings also propose the potential application of ebselen in the prevention and treatment of aging-related disorders, including late-onset hypogonadism.

Date: 2025
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DOI: 10.1038/s41467-025-65328-4

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