Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression

Ming Yu; Yali Yang; Hao Zhao; Mengxia Li; Jie Chen; Baobei Wang; Tianxia Xiao; Chen Huang; Huashan Zhao; Wei Zhou; Jian V Zhang

doi:10.3389/fphar.2022.985618

Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression

Front Pharmacol. 2022 Nov 29:13:985618. doi: 10.3389/fphar.2022.985618. eCollection 2022.

Authors

Ming Yu^{1

2

3}, Yali Yang^{1

2

3

4}, Hao Zhao⁵, Mengxia Li^{1

2

3}, Jie Chen^{1

2

3}, Baobei Wang^{1

2

3}, Tianxia Xiao^{1

2

3}, Chen Huang^{1

2

3}, Huashan Zhao^{1

2

3}, Wei Zhou⁶, Jian V Zhang^{1

2

3}

Affiliations

¹ Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
² Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
³ Shenzhen Key Laboratory of Metabolic Health, Shenzhen, China.
⁴ Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen, China.
⁵ College of Life Science, Northeast Forestry University, Harbin, China.
⁶ Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.

Abstract

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.

Keywords: CMKLR1; chemerin; endometriosis; small molecule antagonist; α-NETA.