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This review focuses on the preclinically supported immune-inflammatory interactions between the testicular and penile microenvironments in varicocele patients, systematically summarizing the plausible and partially validated molecular mechanisms mediating erectile dysfunction and spermatogenic impairment. We explore the network relationships among local and systemic inflammatory cytokines, immune cell infiltration, oxidative stress, endothelial dysfunction, and neurovascular injury. By integrating recent omics studies, animal models, and available clinical data, this article elucidates the hypothetical and mechanistically plausible pathological linkage from abnormal varicose veins in the pampiniform plexus to distal impairment of penile cavernous function. The review aims to synthesize and contextualize the systemic impact of varicocele and to establish a theoretical foundation for developing targeted therapies addressing immune-inflammatory pathways.<\/jats:p>","DOI":"10.3389\/fendo.2026.1813721","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T04:46:29Z","timestamp":1779684389000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Advances in immune-inflammatory interactions within the testicular-penile microenvironment of varicocele patients: molecular mechanisms underlying erectile dysfunction and spermatogenic impairment"],"prefix":"10.3389","volume":"17","author":[{"given":"Gaoyuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine, The 960th Hospital of the PLA Joint Logistics Support Force","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Yu","sequence":"additional","affiliation":[{"name":"First Department of Cadre Ward, The 960th Hospital of the PLA Joint Logistics Support Force","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2012.197","article-title":"Insight into oxidative stress in varicocele-associated male infertility: part 1","volume":"9","author":"Agarwal","year":"2012","journal-title":"Nat Rev Urol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/nrurol.2012.198","article-title":"Insight into oxidative stress in varicocele-associated male infertility: part 2","volume":"10","author":"Hamada","year":"2013","journal-title":"Nat Rev Urol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.729539","article-title":"Varicocele-mediated male infertility: from the perspective of testicular immunity and inflammation","volume":"12","author":"Fang","year":"2021","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4103\/aja202488","article-title":"Research advances in inflammation and oxidative stress in varicocele-induced male infertility: a narrative review","volume":"27","author":"Wang","year":"2025","journal-title":"Asian J Andrology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.2047-2927.2013.00160.x","article-title":"Male fertility and varicocoele: role of immune factors","volume":"2","author":"Bozhedomov","year":"2014","journal-title":"Andrology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4103\/aja.aja_121_18","article-title":"Proteomic analysis of seminal plasma from bilateral varicocele patients indicates an oxidative state and increased inflammatory response","volume":"21","author":"Panner Selvam","year":"2019","journal-title":"Asian J Andrology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232416118","article-title":"Varicocele, functional foods and nutraceuticals: from mechanisms of action in animal models to therapeutic application","volume":"23","author":"Marini","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dei089","article-title":"Varicocele, hypoxia and male infertility. 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