piRNA-46403 Promotes Sertoli Cell Ferroptosis via Disrupting m5C-dependent USP18 mRNA Stabilization in Varicocele-mediated Infertility.

Authors

Xiao Fang, Li Song, Dong Liu, Zhixiang Xin, Wenjuan Pang, Qiang Tong, Jing Huang, Anbang Wang, Lei Yin, Hejing Huang, Aimin Jiang, Shancheng Ren

Published in

International journal of biological sciences. Volume 22. Issue 13. Pages 7295-7315. Epub Aug 12, 2026.

Abstract

Varicocele (VC) represents a primary etiology of male infertility, yet the epigenetic landscapes and molecular triggers driving VC-associated spermatogenic failure remain largely enigmatic. Herein, it is demonstrated that Sertoli cell ferroptosis is a critical pathological feature of VC, and its pharmacological inhibition effectively rescues VC-induced reproductive impairment in vivo. Through small RNA sequencing of clinical testicular tissues, piRNA-46403 is identified as a significantly upregulated mediator in VC patients with asthenospermia. Functionally, piRNA-46403 is shown to orchestrate Sertoli cell ferroptosis, whereas its silencing attenuates spermatogonial apoptosis and restores spermatogenic function. Mechanistically, piRNA-46403 acts as a molecular decoy that binds to the RNA-binding protein YBX1. This interaction disrupts the binding of YBX1 to m5C-modified USP18 mRNA, thereby reducing USP18 mRNA stability and triggering ferroptosis. These findings elucidate a novel piRNA-46403/YBX1/m5C-modified USP18 regulatory axis in the male reproductive system and position piRNA-46403 as a promising therapeutic target for mitigating VC-mediated infertility.

PMID:
42695002
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.