Macrophage-derived IL-6 reprograms lipid metabolism to promote colorectal cancer development through USP14-mediated FASN deubiquitination.

BACKGROUND: Inflammation and metabolic reprogramming are hallmark features of tumors. However, the role of the inflammatory microenvironment in orchestrating lipid metabolic changes and the associated mechanisms remains unclear. This study investigates the impact of macrophage-derived interleukin-6 (IL-6) on lipid metabolism in colorectal cancer and explores the underlying mechanisms. METHODS: Macrophage infiltration was assessed using immunofluorescence. Oil Red O, BODIPY 493/503, and lipidomics measured cellular lipid levels. ELISA quantified cytokine levels secreted by macrophages. Co-immunoprecipitation and Western blot analyzed interactions between ubiquitin-specific-processing protease 14 (USP14) and fatty acid synthase (FASN). ChIP and luciferase assays confirmed signal transducer and activator of transcription 3 (STAT3)’s effect on USP14 transcription. AutodockVina 1.2.2 and cellular thermal shift assay were used to analyze the interaction between USP14 and 6-gingerol. RESULTS: In murine models, macrophage infiltration induced by dextran sodium sulfate (DSS) or lipopolysaccharides (LPS) increased lipid and FASN levels, accelerating colorectal cancer progression. Depletion of macrophages reduced LPS-induced tumor growth and lipid levels. Conditioned medium from macrophages elevated FASN expression and lipid accumulation in CRC cells, effects reversed by anti-IL-6 antibody. IL-6 significantly increased FASN expression and tumor progression in CT26 allograft mice. Mechanistically, IL-6 activated STAT3, which upregulated USP14, thereby stabilizing FASN and promoting lipogenesis. Additionally, we identified 6-gingerol as a USP14 inhibitor that suppresses FASN expression and tumor progression. CONCLUSIONS: Our findings reveal a novel signaling axis involving IL-6, STAT3, USP14, and FASN, activated by macrophage infiltration in colorectal cancer. This study underscores the critical role of IL-6 in enhancing FASN expression, providing potential therapeutic and prognostic strategies for inflammation-related cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07911-x.