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<p>Colorectal cancer (CRC) remains a leading gastrointestinal malignancy and lacks effective adjuvant therapies. Cyclophilin D (CypD), a mitochondrial matrix protein, has a controversial role in tumorigenesis. While prior studies suggest a CypD-CRC link, its precise function and mechanisms remain undefined. Here we clarify whether CypD acts as a driver or suppressor of CRC and explore its therapeutic implications. Using RT-qPCR, Western blotting, and immunofluorescence, we confirmed significant CypD downregulation in CRC tissues/cells versus non-malignant controls. Through in vitro (CCK-8, colony formation, transwell migration, spheroid formation, apoptosis, and autophagy assays) and in vivo tumor xenograft experiments with CypD-knockdown/overexpressing CRC cells (DLD1 and RKO), knocking down CypD promoted, whereas its overexpression inhibited, malignant phenotypes (proliferation, migration, self-renewal, tumorigenicity). Mechanistically, CypD activated protective autophagy and cell apoptosis, with autophagy inhibitor chloroquine reversing this effect. Critically, knocking down CypD attenuated the anti-CRC efficacy of 5-fluorouracil/epigallocatechin-3-gallate combination therapy, whereas its overexpression enhanced therapeutic response. This study provides the first definitive evidence that CypD functions as a tumour suppressor via autophagy-apoptosis crosstalk. Low CypD expression may serve as a biomarker for poor treatment response. Enhancing CypD activity represents a promising strategy to augment existing CRC treatments.</p>

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Cyclophilin D suppresses colorectal cancer progression through the activation of an autophagy-mediated apoptotic pathway

  • 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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  • Ling Zhang,
  • Yi Liu,
  • Ruiqi Liu,
  • Wenjun Wang,
  • Ruiji Li

摘要

Colorectal cancer (CRC) remains a leading gastrointestinal malignancy and lacks effective adjuvant therapies. Cyclophilin D (CypD), a mitochondrial matrix protein, has a controversial role in tumorigenesis. While prior studies suggest a CypD-CRC link, its precise function and mechanisms remain undefined. Here we clarify whether CypD acts as a driver or suppressor of CRC and explore its therapeutic implications. Using RT-qPCR, Western blotting, and immunofluorescence, we confirmed significant CypD downregulation in CRC tissues/cells versus non-malignant controls. Through in vitro (CCK-8, colony formation, transwell migration, spheroid formation, apoptosis, and autophagy assays) and in vivo tumor xenograft experiments with CypD-knockdown/overexpressing CRC cells (DLD1 and RKO), knocking down CypD promoted, whereas its overexpression inhibited, malignant phenotypes (proliferation, migration, self-renewal, tumorigenicity). Mechanistically, CypD activated protective autophagy and cell apoptosis, with autophagy inhibitor chloroquine reversing this effect. Critically, knocking down CypD attenuated the anti-CRC efficacy of 5-fluorouracil/epigallocatechin-3-gallate combination therapy, whereas its overexpression enhanced therapeutic response. This study provides the first definitive evidence that CypD functions as a tumour suppressor via autophagy-apoptosis crosstalk. Low CypD expression may serve as a biomarker for poor treatment response. Enhancing CypD activity represents a promising strategy to augment existing CRC treatments.