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Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.<\/jats:p><\/jats:sec>OBJECTIVE AND RATIONALE<\/jats:title>We summarize the functional roles of autophagy in the pre-testicular (hypothalamic\u2013pituitary\u2013testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.<\/jats:p><\/jats:sec>SEARCH METHODS<\/jats:title>In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: \u2018autophagy\u2019, \u2018sperm\u2019, \u2018hypothalamic\u2013pituitary\u2013testis axis\u2019, \u2018spermatogenesis\u2019, \u2018spermatocytogenesis\u2019, \u2018spermatidogenesis\u2019, \u2018spermiogenesis\u2019, \u2018spermiation\u2019, \u2018sperm maturation\u2019, \u2018fertilization\u2019, \u2018capacitation\u2019 and \u2018acrosome\u2019 in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as \u2018bafilomycin A1\u2019, \u2018chloroquine\u2019, \u2018hydroxychloroquine\u2019, \u20183-Methyl Adenine (3-MA)\u2019, \u2018lucanthone\u2019, \u2018wortmannin\u2019 and autophagy activators such as \u2018rapamycin\u2019, \u2018perifosine\u2019, \u2018metformin\u2019 in combination with \u2018disease\u2019, \u2018treatment\u2019, \u2018therapy\u2019, \u2018male infertility\u2019 and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.<\/jats:p><\/jats:sec>OUTCOMES<\/jats:title>(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.<\/jats:p><\/jats:sec>WIDER IMPLICATIONS<\/jats:title>Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.<\/jats:p><\/jats:sec>","DOI":"10.1093\/humupd\/dmab043","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T20:21:03Z","timestamp":1638908463000},"page":"200-231","source":"Crossref","is-referenced-by-count":142,"title":["Autophagy: a multifaceted player in the fate of sperm"],"prefix":"10.1093","volume":"28","author":[{"given":"Mei","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China"},{"name":"Harvard Reproductive Endocrine Science Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zeng","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China"},{"name":"Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China"},{"name":"Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. 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