Li Han, Chai Xiaoshan
Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, No.139, Renmin Middle Road, Furong District, Changsha 410011, China.
Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, No.139, Renmin Middle Road, Furong District, Changsha 410011, China.
Cell Signal. 2025 Jun 4;134:111922. doi: 10.1016/j.cellsig.2025.111922.
Macrophage M2 polarization plays a critical role in the progression of endometriosis (EMS), and glycolysis has emerged as a potential therapeutic target. This study aimed to investigate the interplay between glycolytic signaling and macrophage M2 polarization in EMS.
Clinical correlations were analyzed in ectopic endometrial tissues from EMS patients. Primary endometrial stromal cells (ESCs) and Ishikawa cells were cultured under hypoxic conditions, and their conditioned media were used to treat THP-1-derived macrophages. Mechanistic investigations were performed through PDPK1 knockdown, AKT/CD47 overexpression, and lactic acid (LA) supplementation, and the therapeutic potential was assessed in a mouse model of EMS treated with PDPK1, CD47, and LDHA inhibitors.
Ectopic EMS tissues exhibited increased infiltration of CD206 M2 macrophages, which positively correlated with upregulation of CD47, PDPK1, and LDHA. Hypoxia enhanced the proliferation and migration of endometrial cells, accompanied by activation of the AKT/mTOR pathway and glycolytic reprogramming, as indicated by elevated glucose uptake, LA, and ATP production, and elevated expression of GLUT1, PDK1, and PKM2. Moreover, hypoxia promoted M2 polarization of THP-1-derived macrophages, evidenced by an increased CD206 population, a disrupted M1/M2 ratio, reduced pro-inflammatory cytokines (IL-6, TNF-α), and elevated anti-inflammatory factors (IL-10, TGF-β). Silencing of PDPK1 attenuated hypoxia-induced AKT/mTOR activation and CD47/LDHA expression, thereby reducing glycolysis and M2 polarization. These effects were restored by AKT/CD47 overexpression or exogenous LA supplementation. In vivo, pharmacological inhibition of PDPK1, CD47, or LDHA significantly reduced lesion size, suppressed M2 macrophage infiltration, and promoted apoptosis.
PDPK1 promotes M2 polarization via CD47/AKT-LDHA-mediated glycolytic reprogramming, thereby exacerbating EMS progression. Targeting this glycolysis-immune axis could be a promising therapeutic strategy for EMS.
巨噬细胞M2极化在子宫内膜异位症（EMS）进展中起关键作用，糖酵解已成为一个潜在的治疗靶点。本研究旨在探讨EMS中糖酵解信号与巨噬细胞M2极化之间的相互作用。
对EMS患者的异位子宫内膜组织进行临床相关性分析。原代子宫内膜基质细胞（ESC）和 Ishikawa细胞在缺氧条件下培养，其条件培养基用于处理THP-1来源的巨噬细胞。通过敲低PDPK1、过表达AKT/CD47和补充乳酸（LA）进行机制研究，并在用PDPK1、CD47和LDHA抑制剂治疗的EMS小鼠模型中评估治疗潜力。
异位EMS组织中CD206 M2巨噬细胞浸润增加，这与CD47、PDPK1和LDHA的上调呈正相关。缺氧增强了子宫内膜细胞的增殖和迁移，伴随着AKT/mTOR途径的激活和糖酵解重编程，表现为葡萄糖摄取、LA和ATP生成增加，以及GLUT1、PDK1和PKM2表达升高。此外，缺氧促进了THP-1来源巨噬细胞的M2极化，表现为CD206细胞群增加、M1/M2比例失调、促炎细胞因子（IL-6、TNF-α）减少和抗炎因子（IL-10、TGF-β）升高。敲低PDPK1可减弱缺氧诱导的AKT/mTOR激活以及CD47/LDHA表达，从而减少糖酵解和M2极化。AKT/CD47过表达或外源性LA补充可恢复这些作用。在体内，对PDPK1、CD47或LDHA的药理抑制显著减小了病变大小，抑制了M2巨噬细胞浸润，并促进了细胞凋亡。
PDPK1通过CD47/AKT-LDHA介导的糖酵解重编程促进M2极化，从而加剧EMS进展。靶向这一糖酵解-免疫轴可能是EMS的一种有前景的治疗策略。
