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Short peptide perturbs spermatogenesis via immune microenvironment dysregulation and mitochondrial imbalance

Heng Wang,Xiaofang Tan,Deyu Chen

Published 2025 in FEBS Open Bio

ABSTRACT

A short peptide derived from the occludin protein regulates tight junctions (TJ) of the blood–testis barrier and impairs germ cell development. However, the mechanism behind how this peptide regulates TJ and induces cell apoptosis remains unclear. In the present study, an animal model with induced TJ disruption via the short peptide was used to evaluate its impact on spermatogenesis. Here, we demonstrate that the short peptide promoted the infiltration of immune cells into the testicular interstitial tissue, accompanied by upregulation expression of the pro‐inflammatory factors interleukin‐6 and tumor necrosis factor‐α. Moreover, mitochondrial fragmentation and mitophagy were upregulated in Sertoli cells and Leydig cells. Consistently, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed extensive apoptosis in the testes during spermatogenesis. Notably, the severity of these disruptions began to attenuate after 27 days, although full functional recovery was not observed. Our findings reveal a novel mechanism wherein peptide‐induced immune dysregulation and mitochondrial dysfunction synergistically impair spermatogenesis, potentially via microenvironmental perturbation of the TJ. Overall, these findings could hold valuable insights for the development of non‐hormonal male contraceptives.

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