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Background <p>Pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme in proline biosynthesis, has been implicated in various cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains elusive.</p> Methods <p>We analyzed PYCR1 expression and its correlation with clinicopathological features using the UALCAN platform based on TCGA data. Functional roles of PYCR1 in cell proliferation and migration were assessed using CCK-8, colony formation, and wound healing assays in ccRCC cell lines (769P and 786O). The regulatory mechanism of PYCR1 in ferroptosis was investigated through pharmacological induction and molecular biology techniques.</p> Results <p>Pan-cancer analysis revealed significant upregulation of PYCR1 in 22 malignancies, with particularly robust overexpression in ccRCC tissues and cell lines compared to normal controls. High PYCR1 expression was positively correlated with advanced pathological stages, nodal metastasis, and poor prognosis in ccRCC patients. Functionally, PYCR1 overexpression promoted, while its knockdown suppressed, proliferation and migration of ccRCC cells. Mechanistically, PYCR1 was found to inhibit ferroptosis by regulating intracellular iron homeostasis and the antioxidant system: PYCR1 depletion increased intracellular Fe²⁺ accumulation and lipid peroxidation, decreased glutathione (GSH) content, and downregulated key ferroptosis regulators (GPX4, FSP1, SLC7A11). Importantly, these effects were reversed by proline supplementation, indicating that PYCR1-mediated proline reprogramming is essential for suppressing ferroptosis.</p> Conclusion <p>Our findings indicate that PYCR1 functions as an oncogene in ccRCC to facilitate tumor progression and suppress ferroptosis predominantly via proline synthesis, while other unelucidated parallel regulatory pathways may also participate in this biological process. Hence, PYCR1 is expected to serve as a promising prognostic biomarker and therapeutic candidate for ccRCC.</p>

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PYCR1 modulates ferroptosis and malignant phenotypes of clear cell renal cell carcinoma through proline biosynthesis

  • 期刊论文

  • 发表日期：

    2026年6月23日

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  • Jizhe Zhou,
  • Yuting Zhou,
  • Haifeng Li,
  • Minlin Jiang,
  • Yueyue Guo,
  • Delong Xie,
  • Sangui Yi,
  • Zongling Liu

摘要

Background

Pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme in proline biosynthesis, has been implicated in various cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains elusive.

Methods

We analyzed PYCR1 expression and its correlation with clinicopathological features using the UALCAN platform based on TCGA data. Functional roles of PYCR1 in cell proliferation and migration were assessed using CCK-8, colony formation, and wound healing assays in ccRCC cell lines (769P and 786O). The regulatory mechanism of PYCR1 in ferroptosis was investigated through pharmacological induction and molecular biology techniques.

Results

Pan-cancer analysis revealed significant upregulation of PYCR1 in 22 malignancies, with particularly robust overexpression in ccRCC tissues and cell lines compared to normal controls. High PYCR1 expression was positively correlated with advanced pathological stages, nodal metastasis, and poor prognosis in ccRCC patients. Functionally, PYCR1 overexpression promoted, while its knockdown suppressed, proliferation and migration of ccRCC cells. Mechanistically, PYCR1 was found to inhibit ferroptosis by regulating intracellular iron homeostasis and the antioxidant system: PYCR1 depletion increased intracellular Fe²⁺ accumulation and lipid peroxidation, decreased glutathione (GSH) content, and downregulated key ferroptosis regulators (GPX4, FSP1, SLC7A11). Importantly, these effects were reversed by proline supplementation, indicating that PYCR1-mediated proline reprogramming is essential for suppressing ferroptosis.

Conclusion

Our findings indicate that PYCR1 functions as an oncogene in ccRCC to facilitate tumor progression and suppress ferroptosis predominantly via proline synthesis, while other unelucidated parallel regulatory pathways may also participate in this biological process. Hence, PYCR1 is expected to serve as a promising prognostic biomarker and therapeutic candidate for ccRCC.