LRRC71 is essential for sperm motility, fertilization, and male fertility.

Although sperm supply half the genomic material necessary for generating viable offspring in sexual reproduction, the core molecular mechanisms underlying their formation remain largely unelucidated. Here, we demonstrate that leucine-rich repeat-containing 71 (LRRC71) is essential for spermatogenesis and male fertility in mice. Lrrc71 knockout (KO) mice exhibit asthenozoospermia and disrupted mitochondrial sheaths in sperm. Both glycolysis and oxidative phosphorylation (OXPHOS) pathways were disrupted in Lrrc71 KO sperm, resulting in reduced ATP content. Furthermore, Lrrc71 KO sperm showed defective fertilization capacity and failed sperm migration into the oviduct. Key metabolic enzymes and fertilization-related proteins were significantly down-regulated in Lrrc71 KO sperm, and co-immunoprecipitation validated their interactions with LRRC71. Also, a novel heterozygous variant of LRRC71 was identified in a patient with asthenozoospermia. Despite failed in vitro fertilization (IVF), a successful intracytoplasmic sperm injection outcome was achieved in Lrrc71 KO mice. These findings demonstrate the essential role of LRRC71 in regulating spermatogenesis and sperm function, which facilitates our understanding of the molecular mechanisms underlying spermatogenesis. LRRC71 represents a potential target for the diagnosis and treatment of male infertility associated with asthenozoospermia.