ABSTRACT Age‐related male hypogonadism is often associated with obesity‐related metabolic disorders and impaired regulation of the testicular anti‐inflammatory microenvironment. However, how adipose‐mediated signals intersect with local testicular immunity remains unclear. In this study, single‐cell RNA sequencing (scRNA‐seq) of human and mouse testes identified a conserved CD206 Lo MHCII Hi macrophage subset, which undergoes CMKLR1‐mediated metabolic reprogramming toward glycolysis and pro‐inflammatory state during middle age. This immunometabolic shift is further found to impair spermatogenesis. CMKLR1 is identified as a viable target in vivo for restoring immunometabolic balance in aging testes. Systemic administration of a newly developed CMKLR1 antagonist peptide (P12C5) or non‐pharmacological intervention such as high‐intensity interval training (HIIT) rescued spermatogenesis in middle‐aged humans and mice, and reversed the pro‐inflammatory immunometabolic phenotype in testicular macrophages. Together, these findings validate CMKLR1 as a key modulator of testicular immunometabolism and a therapeutic target for mitigating age‐related immunometabolic dysfunction.
Zhu et al. (Thu,) studied this question.