Luteolin Ameliorates Testis Injury and Blood–Testis Barrier Disruption through the Nrf2 Signaling Pathway and by Upregulating Cx43

Scope: Luteolin, a natural flavonoid, displays protective activities to testicular tissue. However, the molecular mechanisms are still unclear. In this study, the aim is to identify the protective effects and underlying mechanisms of luteolin against triptolide (TP)-induced damage of testicular tissue. Methods and results: Pre-incubation of Sertoli cells (SCs) with luteolin results in a significant reduction of TP-induced apoptotic cells, which occurs concomitantly with the effective inhibition of reactive oxygen species accumulation. Luteolin results in a significant reduction in testicular damage and spermatogenesis dysfunction in a mouse model of testicular damage. Mechanistic studies reveal that luteolin significantly triggers Nrf2 translocation, increases antioxidant response element-luciferase reporter activity, and induces antioxidant enzyme expression. Nrf2 siRNA reduces luteolin-induced protection in SCs. Besides inhibiting apoptosis, luteolin recovers the blood–testis barrier (BTB) integrity by upregulating connexin43 (Cx43) expression. Moreover, specifically blocked Cx43 activity completely blocks repairmen of luteolin to BTB values. In accordance with in vitro results, luteolin suppresses testicular injury and spermatogenesis dysfunction by activation of Nrf2 and Cx43 in a testicular injury model. Conclusion: Luteolin is identified as a novel active ingredient that contributes to the protective activity in testicular damage through activating the Nrf2 signaling pathway and by upregulating Cx43.