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<p>Colorectal cancer (CRC) is a prevalent malignant tumor, and its pathogenesis has not yet been fully elucidated. The tumor microenvironment (TME) and ferroptosis in cancer cells are key drivers of tumor progression and metastasis. This research revealed that elevated INHBA expression in CRC tissues correlates with unfavorable clinical outcomes. In vitro and in vivo studies demonstrated that elevated INHBA enhances CRC cellular growth, migration, and invasion, whereas INHBA knockdown inhibits these malignant biological behaviors. Further investigation revealed that INHBA drives malignancy by reprogramming tumor-associated macrophages (TAMs) toward the M2 phenotype in the TME and by inhibiting mitochondrial-dependent ferroptosis in CRC cells. Mechanistically, INHBA upregulates SLC25A10 to activate the succinate/SUCNR1 axis, thus facilitating M2-like TAM polarization. It also activates the mitochondrial glutathione (mtGSH)/glutathione peroxidase 4 (GPX4) pathway to suppress mitochondria-dependent ferroptosis in CRC cells. Additionally, INHBA acts as a scaffold protein to inhibit TRIM21-mediated ubiquitination and degradation of SLC25A10, thereby stabilizing the SLC25A10 protein. In summary, INHBA drives tumor progression by remodeling the immune microenvironment and antagonizing ferroptosis in CRC cells, providing a theoretical basis for developing INHBA-targeted inhibitors or combined immunoferroptosis therapeutic strategies.</p><p></p>

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Inhibin beta A drives colorectal cancer progression through macrophage M2 polarization and mitochondria-dependent ferroptosis suppression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Wentao Li,
  • Lin Liang,
  • Siyi Liu,
  • Jingqiong Tang,
  • Shuangyan Ou,
  • Zhijun Yuan,
  • Yanhong Zhou,
  • Xia Yuan

摘要

Colorectal cancer (CRC) is a prevalent malignant tumor, and its pathogenesis has not yet been fully elucidated. The tumor microenvironment (TME) and ferroptosis in cancer cells are key drivers of tumor progression and metastasis. This research revealed that elevated INHBA expression in CRC tissues correlates with unfavorable clinical outcomes. In vitro and in vivo studies demonstrated that elevated INHBA enhances CRC cellular growth, migration, and invasion, whereas INHBA knockdown inhibits these malignant biological behaviors. Further investigation revealed that INHBA drives malignancy by reprogramming tumor-associated macrophages (TAMs) toward the M2 phenotype in the TME and by inhibiting mitochondrial-dependent ferroptosis in CRC cells. Mechanistically, INHBA upregulates SLC25A10 to activate the succinate/SUCNR1 axis, thus facilitating M2-like TAM polarization. It also activates the mitochondrial glutathione (mtGSH)/glutathione peroxidase 4 (GPX4) pathway to suppress mitochondria-dependent ferroptosis in CRC cells. Additionally, INHBA acts as a scaffold protein to inhibit TRIM21-mediated ubiquitination and degradation of SLC25A10, thereby stabilizing the SLC25A10 protein. In summary, INHBA drives tumor progression by remodeling the immune microenvironment and antagonizing ferroptosis in CRC cells, providing a theoretical basis for developing INHBA-targeted inhibitors or combined immunoferroptosis therapeutic strategies.