This study reveals the epigenetic mechanism by which GOLM1 in tumor-associated macrophages regulates the secretion of EFEMP1, providing novel experimental design strategies for targeting the tumor microenvironment. It offers valuable insights for combination therapies, particularly in tumors involving the EGFR signaling pathway.
Literature Overview
The article titled "The GOLM1-ACLY pathway regulates macrophage-secreted EFEMP1 via H3K27ac modifications to drive tumor progression," published in the Journal of Advanced Research, systematically investigates the non-cell-autonomous regulatory role of macrophage-derived GOLM1 in the tumor microenvironment. The study reveals that GOLM1 interferes with the phosphorylation of ACLY, thereby inhibiting histone H3K27 acetylation, promoting EFEMP1 transcription and secretion, and ultimately activating the EGFR-MAPK/AKT signaling pathway in tumor cells. This mechanism highlights the critical role of the macrophage metabolism-epigenetics-secretion axis in tumor progression and deepens our understanding of stromal-tumor cell interactions within the tumor immune microenvironment (TIME).Background Knowledge
Currently, the treatment of solid tumors such as hepatocellular carcinoma (HCC) and lung cancer still faces major challenges, including immunosuppressive microenvironments and targeted therapy resistance. As a major component of TIME, tumor-associated macrophages (TAMs) and their pro-tumorigenic functions have become important therapeutic targets. However, precisely targeting the pro-tumor TAM subsets while avoiding systemic immunosuppression remains a bottleneck in cancer immunotherapy. Most existing studies focus on surface markers such as CD206 and PD-L1, but the deeper mechanisms by which TAMs regulate tumor cells through secreted factors—especially the coupling between metabolic reprogramming and epigenetic regulation—remain poorly understood. This study uses GOLM1 as an entry point to explore its novel functions in macrophages, breaking through the previous notion that GOLM1 functions only in tumor cells. It reveals a previously unknown pathway in which macrophage metabolism regulates EFEMP1 via the ACLY-H3K27ac axis, offering a new dimension for TAM-targeted therapeutic strategies.
Research Methods and Experiments
The authors employed multiple animal models for in vivo validation, including an orthotopic liver cancer model (Hepa1-6 cell injection) and a nude mouse subcutaneous xenograft model (co-inoculation of Huh7 and THP1 cells), combined with an AAV9-F4/80 promoter-driven macrophage-specific Golm1 overexpression system to clarify the pro-tumor role of GOLM1 in macrophages. By generating Golm1fl/fl;Lyz2Cre conditional knockout mice, they demonstrated that macrophage-specific deletion of Golm1 significantly suppresses tumor growth. In vitro, CRISPR-Cas9 was used to construct a Golm1-knockout THP1 cell line, which was co-cultured with tumor cells to assess changes in proliferation, metabolism, and stemness. Co-immunoprecipitation (Co-IP) and IP-MS analyses identified ACLY as a GOLM1-interacting protein, with phosphorylation at the S455 site confirmed using phospho-specific antibodies. Furthermore, integrated CUT&Tag-seq and RNA-seq analyses revealed changes in H3K27ac enrichment at the Efemp1 gene promoter region, and ELISA confirmed EFEMP1 secretion levels in the supernatant.Key Conclusions and Perspectives
Research Significance and Prospects
This study directly links metabolic regulation and epigenetic reprogramming in macrophages, proposing a novel GOLM1-ACLY-H3K27ac-EFEMP1 signaling axis that provides a paradigm for understanding the 'metabolism-epigenetics-secretion' network in the tumor microenvironment. From a drug development perspective, GOLM1 or ACLY could serve as potential therapeutic targets, particularly for HCC or lung cancer patients with resistance to EGFR inhibitors. In disease modeling, it is recommended to generate double-transgenic mice with macrophage-specific Golm1 knockout and EFEMP1 reporter genes to dynamically monitor microenvironmental signals. Moreover, given that H3K27ac is a reversible modification, epigenetic drugs such as HDAC inhibitors may influence EFEMP1 secretion, which warrants further investigation.
Conclusion
This study systematically reveals the molecular mechanism by which GOLM1 in macrophages regulates EFEMP1 secretion through modulating ACLY phosphorylation and subsequent H3K27ac modifications, ultimately promoting tumor cell proliferation. This finding not only expands the functional repertoire of GOLM1 but also tightly links macrophage metabolism, epigenetic regulation, and tumor progression, providing new targets for microenvironment-targeted interventions in HCC, lung cancer, and related diseases. From bench to bedside, targeting the GOLM1-ACLY axis may enhance the efficacy of existing EGFR-targeted therapies, especially in resistant settings. Meanwhile, as a secreted factor, EFEMP1 holds promise as a liquid biopsy biomarker to aid clinical monitoring. Combined with animal models and molecular detection technologies, future development of small-molecule inhibitors or antibody-based drugs targeting this pathway could advance precision medicine. This work provides a solid theoretical foundation for reshaping the tumor immune microenvironment and enabling combination therapies, representing a significant step toward personalized immuno-metabolic cancer treatment.
