Single‐Cell Insights Into Pathogenic Profile of Orchitis and SREBP2‐Associated Cholesterol Dysregulation in Spermatogenic Failure

ABSTRACT

Orchitis, a testicular inflammation often triggered by infection, is a major cause of male infertility due to disruption of the testicular immune microenvironment and progressive loss of germ cells. Currently, no effective or targeted therapies are available. Here, we profile 66,147 single‐cell transcriptomes from testes of orchitis patients and healthy controls, complemented by histological validation. We observe profound remodeling of testicular cell composition, with marked infiltration of CD8 ⁺ effector T cells and inflammatory macrophages, accompanied by germ cell loss. Undifferentiated spermatogonia exhibit cell‐cycle arrest, while somatic cell populations display fibrosis, apoptosis, and loss of homeostatic functions. Notably, interstitial cells show SREBP2‐ associated reprogramming of cholesterol metabolism, characterized by increased synthesis. Inhibition of SREBP2 in a mouse orchitis model improves spermatogenesis, reduces lipid accumulation, and alleviates fibrosis. These findings demonstrate that immune activation–induced SREBP2 upregulation drives cholesterol metabolic imbalance and spermatogenic failure in orchitis, offering potential therapeutic options for inflammation‐associated male infertility.