Advances in immune-inflammatory interactions within the testicular-penile microenvironment of varicocele patients: molecular mechanisms underlying erectile dysfunction and spermatogenic impairment

Varicocele is a prevalent cause of male infertility and has been associated with erectile dysfunction in clinical and preclinical studies, characterized by a complex pathophysiological process involving immune-inflammatory responses. 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.