MXRA7 attenuates sperm injury from exercise-induced fatigue via suppression of epididymal inflammation

Exercise-induced fatigue (EIF) is closely associated with male reproductive dysfunction, but the underlying mechanism remains unclear. This study aimed to explore whether EIF induces oxidative stress and epididymal inflammation, and to clarify the protective role and regulatory pathway of matrix remodeling-associated 7 (MXRA7). Clinical samples from EIF volunteers and an EIF mouse model were used to detect oxidative stress, inflammation, and sperm quality. Mouse caput epididymal PC-1 cells and cauda epididymal DC-2 cells were cultured to establish inflammatory injury models. MXRA7 expression, localization, and function were analyzed by transcriptomic analysis, gene knockdown/overexpression, Western blotting, immunofluorescence, co-immunoprecipitation, and in vitro phosphorylation assays. The results showed that EIF significantly elevated systemic and epididymal oxidative stress and inflammatory responses in both humans and mice, accompanied by impaired sperm motility and epididymal dysfunction. MXRA7 was highly expressed in epididymal epithelial cells, especially in the cauda epididymis, and its expression was negatively correlated with the severity of inflammation. MXRA7 knockdown aggravated inflammatory injury in DC-2 cells, whereas MXRA7 overexpression suppressed oxidative stress, inflammatory factor release, and NF-κB signaling activation. Mechanistically, protein kinase C alpha (PKCα) mediated the expression and phosphorylation of MXRA7, and MXRA7 further inhibited the NF-κB pathway to alleviate epididymal inflammation. In addition, MXRA7 expressed by cauda epididymal epithelial cells directly protected sperm from inflammatory damage. In conclusion, EIF impairs sperm function by triggering epididymal oxidative stress and inflammatory injury. MXRA7, regulated by PKCα-mediated phosphorylation, serves as a key protective factor that attenuates EIF-induced epididymal inflammation via inhibiting the NF-κB signaling pathway. This study provides a novel target for the prevention and treatment of reproductive damage caused by excessive exercise.