PDPK1 governs macrophage M2 polarization via hypoxia-driven CD47/AKT-glycolytic Axis in endometriosis

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Endometriosis; Glycolysis; Macrophage polarization; PDPK1-CD47/AKT-LDHA axis.