# Targeting the CMKLR1‐Mediated Signaling Rebalances Immunometabolism State in Middle‐Age Testicular Macrophages

## TL;DR

This study shows that targeting CMKLR1 in testicular macrophages can reverse age-related inflammation and improve sperm production in middle-aged individuals.

## Contribution

The study identifies CMKLR1 as a novel therapeutic target for age-related testicular immunometabolic dysfunction.

## Key findings

- CMKLR1 mediates metabolic reprogramming of testicular macrophages toward a pro-inflammatory state in middle age.
- Inhibiting CMKLR1 or using HIIT restores immunometabolic balance and improves spermatogenesis in middle-aged mice and humans.
- Adipose signals linked to high BMI contribute to the pro-inflammatory profile of testicular macrophages.

## 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 CD206LoMHCIIHi 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.

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.