This study demonstrated significant dysregulation of lipid metabolism in KD, potentially driven by inflammatory responses in monocytes. LPC has emerged as a potential biomarker of KD and provides new insights into its early diagnosis.

In middle age, testicular CMKLR1⁺ macrophages exhibited a pro-inflammatory immunometabolic profile, mediated by adipose signals associated with high BMI. However, inhibition of CMKLR1 signaling, either through Cmklr1 genetic ablation or treatment with a CMKLR1 antagonist peptide, can reverse this phenotype. Notably, high-intensity interval training (HIIT), as a non-pharmacological intervention, also restored immunometabolic homeostasis by targeting CMKLR1 + testicular macrophages and mitigating the pro-inflammatory state. 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.

Metabolic regulation of immune function is a complex and dynamic process. This Perspective highlights how systems biology approaches, including multi-omics profiling and perturbomics screening, are…

Metabolic regulation of immune function is a complex and dynamic process. This Perspective highlights how systems biology approaches, including multi-omics profiling and perturbomics screening, are…

Metabolic regulation of immune function is a complex and dynamic process. This Perspective highlights how systems biology approaches, including multi-omics profiling and perturbomics screening, are…

Metabolites generated by both host and pathogen have a major impact on the severity and outcomes of infection. This Essay investigates how the study of immunometabolism has yielded insight into the…

Metabolites generated by both host and pathogen have a major impact on the severity and outcomes of infection. This Essay investigates how the study of immunometabolism has yielded insight into the…

Metabolites generated by both host and pathogen have a major impact on the severity and outcomes of infection. This Essay investigates how the study of immunometabolism has yielded insight into the…

Functional and metabolic properties of innate-like T cells — namely, iNKT cells, MAIT cells and some γδ T cells — differ from those of conventional T cells. This Review describes how metabolic pathway...