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  3. MC-LR triggers trophoblast ferroptosis at the maternal-fetal interface by directly targeting PKM2 to reprogram metabolism

MC-LR triggers trophoblast ferroptosis at the maternal-fetal interface by directly targeting PKM2 to reprogram metabolism

  • Ecotoxicol Environ Saf. 2025 Nov 15:307:119451. doi: 10.1016/j.ecoenv.2025.119451.
Meihong Guo 1,  Xinrui Li 2,  Jingwen Zhang 2,  Songci Yan 2,  Shaoru Zhang 3,  Yanting Wen 2,  Xiang Zou 4,  Daojuan Wang 5,  Rong Yang 6,  Shuan Wang 7,  Xiaotian Chen 7,  Jiang Wu 8,  Yong Wang 9
Affiliations

Affiliations

  • 1 Department of Clinical Nutrition, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 2 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 3 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; The People's Hospital of Danyang & Affiliated Danyang Hospital of Nantong University, Danyang 212300, China.
  • 4 Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China.
  • 5 Department of Pain, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 6 Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 7 Department of Clinical Nutrition, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 8 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; Nanjing University (Suzhou) High-Tech Institute, Suzhou 215123, China. Electronic address: [email protected].
PMID: 41273830 DOI: 10.1016/j.ecoenv.2025.119451
Abstract

Intake of microcystin-leucine arginine (MC-LR) is strongly associated with placenta-derived diseases such as preeclampsia (PE) and fetal growth restriction (FGR). Our population sample data revealed a positive correlation between placental MC-LR content and the severity of Ferroptosis in PE and FGR patients, prompting us to investigate the mechanisms underlying MC-LR-induced placental Ferroptosis. Using placental samples from MC-LR-exposed pregnant mice and an in vitro HTR-8/SVneo cell model, we found that MC-LR significantly induced Ferroptosis in placental tissues and trophoblast cells, manifested by Fe²⁺ accumulation, ROS increase, and mitochondrial dysfunction. Further exploration demonstrated that MC-LR binds to PKM2, blocking its conversion from tetramers to dimers. The reduction in PKM2 dimers impaired its function as a transcriptional coactivator for NRF2, thereby reducing the transcription of GPX4 and GCLC. Concurrently, the increase in PKM2 tetramers enhanced its Pyruvate Kinase activity, making HTR-8/SVneo cells more reliant on glycolysis. Pyridoxine (vitamin B6) intervention restored PKM2 function and reversed the Ferroptosis phenotype, confirming PKM2 as the key target. In conclusion, this study delineates the dual regulatory mechanism of PKM2 in MC-LR-triggered placental Ferroptosis, providing novel perspectives on the environmental hazards linked to placenta-derived diseases.

Keywords

Ferroptosis; GPX4; Glycolysis; Microcystin-LR; NRF2; PKM2; Pyridoxine.

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