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Fucosyltransferase 8-derived circular RNA drives M2 polarization of macrophages through ENO1-TNF signaling axis to promote lung cancer progression

ABSTRACT: CircFUT8 (hsa_circ_0003028) was significantly upregulated in lung cancer tissues, correlating with advanced stages and poor prognosis. It enhanced lung cancer cell proliferation, migration, and invasion while inhibiting apoptosis in cellular and animal models. Mechanistically, circFUT8 directly binds ENO1 to form an RNA-protein complex, promoting M2 macrophage polarization. Silencing circFUT8 reversed these effects by suppressing ENO1 and M2 polarization, inhibiting tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307293 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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Fucosyltransferase 8-derived circular RNA drives M2 polarization of macrophages through ENO1-TNF signaling axis to promote lung cancer progression

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