Cellular signalling · 2026
NUPR1-positive tumor-associated macrophages facilitate the progression of hepatocellular carcinoma via ferroptosis resistance.
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Gu Ruo-Lan, Ma Lu-Yuan, Bi Ran-Ran, Dong Shi-Long, Li Xin-Yang, Liu Ming-Jie, Zhao Qian, Zeng Da-Wu, Shen Chuan, Zhao Cai-Yan
Аннотация
BACKGROUND: Tumor-associated macrophages (TAMs) are major contributors to the immunosuppressive microenvironment of hepatocellular carcinoma (HCC). Nuclear protein 1 (NUPR1) is a stress-responsive regulator implicated in tumor progression; however, whether it functionally controls ferroptosis-associated stress adaptation in TAMs and thereby sustains their immunosuppressive phenotype remains unclear.
PATIENTS AND METHODS: Single-cell RNA sequencing and multiplex immunohistochemistry identified and validated NUPR1-expressing TAMs in human HCC. Pharmacological and genetic approaches assessed macrophage polarization, ferroptosis-associated changes, and tumor-supportive activity. Readouts included lipid peroxidation, Fe2+ accumulation, GPX4 expression and activity, redox homeostasis, and mitochondrial membrane potential. GPX4 rescue and pharmacological ferroptosis modulation evaluated the functional involvement of GPX4-associated ferroptosis resistance. Primary bone marrow-derived macrophages (BMDMs) and an immunocompetent orthotopic HCC model provided additional validation.
RESULTS: NUPR1 was enriched in CD163+ TAMs within HCC tissues. In THP-1-derived macrophages, NUPR1 inhibition enhanced ferroptosis-associated changes and attenuated M2-like polarization and tumor-supportive functions, whereas NUPR1 overexpression produced the opposite effects. GPX4 overexpression partially rescued the ferroptosis-associated and macrophage phenotypic changes induced by NUPR1 silencing, whereas RSL3 attenuated the effects of NUPR1 overexpression. Primary BMDMs supported the macrophage phenotypic findings. In the orthotopic model, NUPR1 inhibition suppressed tumor growth and was accompanied by altered macrophage-associated markers and enhanced ferroptosis-associated changes.
CONCLUSION: NUPR1 promotes HCC progression, at least in part, by modulating GPX4-associated ferroptosis-related stress and sustaining the M2-like immunosuppressive phenotype of TAMs.
PATIENTS AND METHODS: Single-cell RNA sequencing and multiplex immunohistochemistry identified and validated NUPR1-expressing TAMs in human HCC. Pharmacological and genetic approaches assessed macrophage polarization, ferroptosis-associated changes, and tumor-supportive activity. Readouts included lipid peroxidation, Fe2+ accumulation, GPX4 expression and activity, redox homeostasis, and mitochondrial membrane potential. GPX4 rescue and pharmacological ferroptosis modulation evaluated the functional involvement of GPX4-associated ferroptosis resistance. Primary bone marrow-derived macrophages (BMDMs) and an immunocompetent orthotopic HCC model provided additional validation.
RESULTS: NUPR1 was enriched in CD163+ TAMs within HCC tissues. In THP-1-derived macrophages, NUPR1 inhibition enhanced ferroptosis-associated changes and attenuated M2-like polarization and tumor-supportive functions, whereas NUPR1 overexpression produced the opposite effects. GPX4 overexpression partially rescued the ferroptosis-associated and macrophage phenotypic changes induced by NUPR1 silencing, whereas RSL3 attenuated the effects of NUPR1 overexpression. Primary BMDMs supported the macrophage phenotypic findings. In the orthotopic model, NUPR1 inhibition suppressed tumor growth and was accompanied by altered macrophage-associated markers and enhanced ferroptosis-associated changes.
CONCLUSION: NUPR1 promotes HCC progression, at least in part, by modulating GPX4-associated ferroptosis-related stress and sustaining the M2-like immunosuppressive phenotype of TAMs.