Multi‐Omics Analysis Reveals That the MAZ / HDGF Regulatory Axis Drives High‐Grade Serous Ovarian Cancer Progression by Modulating Glycolysis and M2 Macrophage Polarization

ABSTRACT Super‐enhancers (SEs) are large clusters of enhancers that drive high‐level expression of genes critical for normal development and tumorigenesis. However, their precise roles in high‐grade serous ovarian carcinoma (HGSOC) remain unclear. This study integrated SE‐derived regulatory networks with proteomic profiles to identify key pro‐tumorigenic signaling in HGSOC progression. Weighted gene co‐expression network analysis (WGCNA) and machine learning were used to screen SE‐driven core oncoproteins. The influence on cell phenotypes was evaluated by detecting invasion, proliferation, apoptosis, glucose consumption, lactate generation, and tube formation. M2 macrophage polarization was assessed by detecting CD163 + cell proportion and TGF‐β1 and IL‐10 secretion. The MAZ/HDGF interaction was confirmed by luciferase and ChIP‐qPCR assays. Xenograft studies were used to evaluate the in vivo function. HDGF was overexpressed and was identified as a core SE‐driven oncoprotein in HGSOC. Silencing of HDGF inhibited the invasion, proliferation, and glycolysis of HGSOC cells, promoted their apoptosis, and attenuated HUVEC tube formation and M2 macrophage polarization. Mechanistically, MAZ transcriptionally activated HDGF through promoter binding. Moreover, HDGF re‐expression counteracted the suppressive effects of MAZ knockdown on HGSOC cell malignant behaviors, HUVEC tube formation, M2 macrophage polarization, and the growth of xenograft tumors. In conclusion, our study unveils the MAZ/HDGF axis as a novel SE‐mediated oncogenic pathway in HGSOC, providing previously unrecognized insights into SE‐driven oncogenesis and highlighting potential targets for HGSOC treatment.