Nanoparticle-based serine replenishment rescues SP1-BNIP3 mitophagy and ameliorates preeclampsia in preclinical models

  • Cell Rep Med. 2026 Jun 16;7(6):102826. doi: 10.1016/j.xcrm.2026.102826.
Yinan Wang  1 ,  Qiongjie Zhou  2 ,  Huanqiang Zhao  3 ,  Zhilin Liu  4 ,  Wei Li  5 ,  Meng Xu  6 ,  Jiangyuan Du  1 ,  Yinfei Chen  1 ,  Wei Cheng  1 ,  Xinping Ng  1 ,  Wenhan Zhou  1 ,  Xinyan Zhang  1 ,  Yan Lin  6 ,  Wei Xu  7 ,  Shimin Zhao  8 ,  Yiyuan Yuan  9 ,  Xiaotian Li  10
Affiliations
  • 1. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China.
  • 2. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China; Shanghai Jiai Genetic & IVF Insitute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200090, P.R. China.
  • 3. Shenzhen Maternity and Child Healthcare Hospital, Women and Children's Medical Center, Southern Medical University, Shenzhen, 518028, Guangdong Province, P.R. China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, 518000, Guangdong, P.R. China; Shenzhen Clinical Research Center for Obstetrics & Gynecology and Reproductive System Diseases, Shenzhen 518000, Guangdong, P.R. China; Asian Academy of Anti-aging Research and Translational Medicine (Shenzhen) Co., Ltd, Shenzhen, 518000, Guangdong, P.R. China.
  • 4. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Changchun, 130022, P.R. China.
  • 5. Laboratory of RNA Epigenetics, Shanghai Medical College, Fudan University, Shanghai, 200030, P.R. China.
  • 6. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, P.R. China.
  • 7. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, P.R. China.
  • 8. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, P.R. China. Electronic address: [email protected].
  • 9. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China. Electronic address: [email protected].
  • 10. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, 200433, Shanghai, China; Shenzhen Maternity and Child Healthcare Hospital, Women and Children's Medical Center, Southern Medical University, Shenzhen, 518028, Guangdong Province, P.R. China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, 518000, Guangdong, P.R. China; Shenzhen Clinical Research Center for Obstetrics & Gynecology and Reproductive System Diseases, Shenzhen 518000, Guangdong, P.R. China; Asian Academy of Anti-aging Research and Translational Medicine (Shenzhen) Co., Ltd, Shenzhen, 518000, Guangdong, P.R. China. Electronic address: [email protected].
PMID: 42167246 DOI: 10.1016/j.xcrm.2026.102826
Abstract

Preeclampsia (PE) is a devastating hypertensive disorder affecting pregnant women worldwide. Disrupted metabolic reprogramming is recognized as a key feature of placental dysfunction in PE, yet the abnormal metabolic adaption and underlying mechanisms remain largely unknown. In this study, we perform targeted metabolomic profiling and identify placental serine deficiency as a hallmark metabolic alteration in PE, which favors PE occurrence. Serine-deficient chow exacerbates PE-like symptoms, such as hypertension and proteinuria, in mice. Mechanistically, serine deficiency attenuates SAM-dependent methylation, decreasing SP1 levels and impairing SP1-BNIP3-mediated Mitophagy, thereby exacerbating oxidative stress to cause placental dysfunction. Notably, targeting serine to the placenta using mPEG5k-poly(D/L-serine) effectively relieves PE-like symptoms in the mouse model. Our findings elucidate an unknown serine-deficiency-mediated metabolic reprogramming in PE and suggest manipulating serine supplementation as a promising translational strategy for PE treatment.

Keywords
mPEG5k-Poly(D/L-serine); mitophagy; preeclampsia; serine deficiency.
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