en <p>Background: Azoospermia, the complete absence of sperm in the ejaculate, is a major cause of male infertility. Sertoli cells are essential for spermatogenesis, and disruptions in innate immune immune pathways, particularly Toll-like receptors (TLRs), may impair their function. This study investigated the expression of TLR1&ndash;10 and downstream signaling molecules (MYD88, NFKB, TRIF, IRF3, and TRAM) in Sertoli cells of azoospermic patients.<br /> Methods: Testicular tissue were collected from 20 azoospermic men undergoing testicular sperm extraction (TESE). Patients were categorized into two TESE positive (sperm present, n=10) and TESE negative (sperm absent, n=10). Sertoli cells were isolated using enzyme digestion and purified via fluorescence-activated cell sorting (FACS). Gene expression of TLR1&ndash;10 and signaling molecules was quantified by RT-PCR. Data were analyzed using independent-samples T-test, with significance set at p&lt;0.05.&nbsp;<br /> Results: Significant downregulation was detected in TLR10 (20.6-fold, p&lt;0.0001), TLR9 (4.6-fold, p&lt;0.05), TLR7 (4.8-fold, p&lt;0.01), TLR6 (12.4-fold, p&lt;0.05), TLR5 (13.5-fold, p&lt;0.001), TLR4 (3.2-fold, p&lt;0.05), and TLR3 (3.1-fold, p&lt;0.01). Among signaling molecules, MYD88 (4.1-fold, p&lt;0.01) and IRF3 (4.2-fold, p&lt;0.05) showed significant reductions, indicating impaired immune signaling in Sertoli cells of TESE-negative men.<br /> Conclusion: Altered expression of TLRs and associated signaling molecules in Sertoli cells of azoospermic men suggests innate immune dysregulation as a potential mecha-nism underlying defective spermatogenesis. These findings highlight immune privilege-associated pathways as possible targets for developing diagnostic biomarkers and novel therapeutic approaches for male infertility.</p> Azoospermia, Male infertility, Signal transduction, Sertoli cells, TESE, Toll-like receptors 109 119 https://www.jri.ir/article/140266 https://www.jri.ir/documents/fullpaper/en/140266.pdf Mohammad RezaLakpourDepartment of Gerontology, Shahid Beheshti University of Medical Sciences Branch, ACECR, Tehran, Iran122863RezaAflatoonianDepartment of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran1660Mohammad AliSadighi GilaniDepartment of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran112410RezaHajihosseiniDepartment of Biology, Payame Noor University, Tehran, Iranhosseini@pnu.ac.ir122864MarjanSabbaghianDepartment of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iranm.sabbaghian@royaninstitue.org122637