Proline-PRODH metabolism promotes placental angiogenesis via the mtROS-STAT3-bFGF/VEGF-A axis

Shuangbo Huang; Deyuan Wu; Zhihui Chen; Chengjun Hu; Kaidi Ma; Jie Peng; Yulong Yin; Chengquan Tan

doi:10.59717/j.xinn-life.2026.100233

The Innovation Life > 2026 Vol. 4 > No. 3 > 100233

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Proline-PRODH metabolism promotes placental angiogenesis via the mtROS-STAT3-bFGF/VEGF-A axis

1.
State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
2.
College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
3.
Engineering Research Center for Animal Breeding and Sustainable Production, Fujian Agriculture and Forestry University, Fuzhou 350002, China
4.
Tropical Crop Genetic Resource Research Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China
5.
College of Animal Science and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
6.
Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China

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Corresponding authors: pengjie@zhku.edu.cn (J.P.); yinyulong@isa.ac.cn (Y.Y.); tanchengquan@scau.edu.cn (C.T.)
Received Date: December 04, 2025

Accepted Date: June 26, 2026

Published Online: June 30, 2026

The Innovation Life 4(3), https://doi.org/10.59717/j.xinn-life.2026.100233 | Cite this article

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GRAPHICAL ABSTRACT

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Dietary proline (Pro) deficiency damages placental angiogenesis and raises low birth weight risk.
  
  Proline regulates placental angiogenesis via mitochondrial reactive oxygen species (mtROS).
  
  mtROS regulates the activation of signal transducer and activator of transcription 3 and angiogenic factors.
  
  Pro dehydrogenase metabolism maintains mtROS homeostasis via sirtuin 1/superoxide dismutase 2 pathways.

ABSTRACT

ABSTRACT

Functional amino acids have been shown to regulate fetal and placental development. However, little is known about the role and mechanism of proline (Pro) in placental angiogenesis. Here, we analyzed amino acid profiles and vascular development in pig placentae at different gestational time points, and found that decreased placental Pro availability was associated with impaired angiogenesis. In a nutrient-restricted mouse model, dietary Pro deficiency reduced placental proline availability, further increased the incidence of low birth weight (LBW), and exacerbated placental vascular defects. Mechanistically, Pro regulates mitochondrial reactive oxygen species (mtROS) homeostasis and subsequently promotes placental angiogenesis through the mediation of phospho-signal transducer and activator of transcription 3 (p-STAT3^Tyr705)-basic fibroblast growth factor (bFGF)/vascular endothelial growth factor A (VEGF-A) pathway. Moreover, Pro-proline dehydrogenase (PRODH) metabolism maintains mtROS homeostasis through glutathione-independent and Sirtuin 1/superoxide dismutase 2-dependent pathways. Collectively, these results demonstrate that dietary Pro plays a crucial role in placental angiogenesis and identify the Pro-PRODH-mtROS- STAT3-bFGF/VEGF-A axis as a potential target for the prevention of LBW.
- Low birth weight /
- Mitochondrial reactive oxygen species /
- Placental angiogenesis /
- Proline metabolism /
- Proline dehydrogenase

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REFERENCES

[1]	Fawzi W. W., Msamanga G. I., Urassa W., et al. (2007). Vitamins and perinatal outcomes among HIV-negative women in Tanzania. N. Engl. J. Med. 356:1423−1431. DOI:10.1056/NEJMoa064868 View in Article CrossRef Google Scholar
[2]	Huang Z., Huang S., Song T., et al. (2021). Placental angiogenesis in mammals: A review of the regulatory effects of signaling pathways and functional nutrients. Adv. Nutr. 12:2415−2434. DOI:10.1093/advances/nmab070 View in Article CrossRef Google Scholar
[3]	Burton G. J. and Jauniaux E. (2018). Pathophysiology of placental-derived fetal growth restriction. Am. J. Obstet. Gynecol. 218:S745−s761. DOI:10.1016/j.ajog.2017.11.577 View in Article CrossRef Google Scholar
[4]	Wu G., Bazer F. W., Datta S., et al. (2008). Proline metabolism in the conceptus: Implications for fetal growth and development. Amino acids 35:691−702. DOI:10.1007/s00726-008-0052-7 View in Article CrossRef Google Scholar
[5]	Yam M., Engel A. L., Wang Y., et al. (2019). Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. J. Biol. Chem. 294:10278−10289. DOI:10.1074/jbc.RA119.007983 View in Article CrossRef Google Scholar
[6]	Krishnan N., Dickman M. B. and Becker D. F. (2008). Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radic. Biol. Med. 44:671−681. DOI:10.1016/j.freeradbiomed.2007.10.054 View in Article CrossRef Google Scholar
[7]	Seiler N. (2000). Ornithine aminotransferase, a potential target for the treatment of hyperammonemias. Curr. drug targets 1:119−153. DOI:10.2174/1389450003349254 View in Article CrossRef Google Scholar
[8]	Adachi R., Okada K., Skene R., et al. (2017). Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline. Biochem. Biophys. Res. Commun. 488:393−399. DOI:10.1016/j.bbrc.2017.05.064 View in Article CrossRef Google Scholar
[9]	Xiong G., Deng L., Zhu J., et al. (2014). Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition. BMC cancer 14:1. DOI:10.1186/1471-2407-14-1 View in Article CrossRef Google Scholar
[10]	Huang S., Li J., Ye H., et al. (2025). Increased proline intake during gestation alleviates obesity-related impaired fetal development and placental function in gilts. Anim. Nutr. 20:355−365. DOI:10.1016/j.aninu.2024.10.007 View in Article CrossRef Google Scholar
[11]	Li K., Cui H., Wang S., et al. (2026). Proline alleviates low-protein diet-induced adverse pregnancy outcomes by enriching akkermansia and activating placental Wnt/Igf1 signaling. J. Agric. Food Chem. 74:9281−9293. DOI:10.1021/acs.jafc.5c12788 View in Article CrossRef Google Scholar
[12]	Wilson M. E., Biensen N. J. and Ford S. P. (1999). Novel insight into the control of litter size in pigs, using placental efficiency as a selection tool. J. Anim. Sci. 77:1654−1658. DOI:10.2527/1999.7771654x View in Article CrossRef Google Scholar
[13]	Colson A., Sonveaux P., Debiève F., et al. (2021). Adaptations of the human placenta to hypoxia: Opportunities for interventions in fetal growth restriction. Hum. Reprod. Update 27:531−569. DOI:10.1093/humupd/dmaa053 View in Article CrossRef Google Scholar
[14]	Huang S., Wu Z., Huang Z., et al. (2021). Maternal supply of cysteamine alleviates oxidative stress and enhances angiogenesis in porcine placenta. J. Anim. Sci. Biotechnol. 12:91. DOI:10.1186/s40104-021-00609-8 View in Article CrossRef Google Scholar
[15]	Wu Z., Xiang Q., Feng L., et al. (2023). Adenosine-ADORA2A promotes ang-induced angiogenesis in intrauterine growth restriction placenta via the stat3/akt pathway. Arterioscler. Thromb. Vasc. Biol. 43:e190−e209. DOI:10.1161/atvbaha.122.318948 View in Article CrossRef Google Scholar
[16]	LeBoeuf S. E., Wu W. L., Karakousi T. R., et al. (2020). Activation of oxidative stress response in cancer generates a druggable dependency on exogenous non-essential amino acids. Cell Metab. 31:339−350.e334. DOI:10.1016/j.cmet.2019.11.012 View in Article CrossRef Google Scholar
[17]	Lewis C. A., Parker S. J., Fiske B. P., et al. (2014). Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55:253−263. DOI:10.1016/j.molcel.2014.05.008 View in Article CrossRef Google Scholar
[18]	Grivennikova V. G., Kareyeva A. V. and Vinogradov A. D. (2018). Oxygen-dependence of mitochondrial ROS production as detected by Amplex Red assay. Redox Biol. 17:192−199. DOI:10.1016/j.redox.2018.04.014 View in Article CrossRef Google Scholar
[19]	Wu G., Bazer F. W., Cudd T. A., et al. (2004). Maternal nutrition and fetal development. J. Nutr. 134:2169−2172. DOI:10.1093/jn/134.9.2169 View in Article CrossRef Google Scholar
[20]	Gu F., Jiang L., Xie L., et al. (2021). Supplementing N-carbamoylglutamate in late gestation increases newborn calf weight by enhanced placental expression of mTOR and angiogenesis factor genes in dairy cows. Anim. Nutr. 7:981−988. DOI:10.1016/j.aninu.2021.05.007 View in Article CrossRef Google Scholar
[21]	Hu C., Wu Z., Huang Z., et al. (2021). Nox2 impairs VEGF-A-induced angiogenesis in placenta via mitochondrial ROS-STAT3 pathway. Redox Biol. 45:102051. DOI:10.1016/j.redox.2021.102051 View in Article CrossRef Google Scholar
[22]	Fukushima K., Murata M., Hachisuga M., et al. (2008). Hypoxia inducible factor 1 alpha regulates matrigel-induced endovascular differentiation under normoxia in a human extravillous trophoblast cell line. Placenta 29:324−331. DOI:10.1016/j.placenta.2008.01.006 View in Article CrossRef Google Scholar
[23]	Armistead B., Kadam L., Drewlo S., et al. (2020). The role of NF-κB in healthy and preeclamptic placenta: Trophoblasts in the spotlight. Int. J. Mol. Sci. 21:1775. DOI:10.3390/ijms21051775 View in Article CrossRef Google Scholar
[24]	Fang K., Sun M., Leng Z., et al. (2023). Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia. J. Exp. Clin. Cancer Res. 42:73. DOI:10.1186/s13046-023-02623-2 View in Article CrossRef Google Scholar
[25]	Chini C. C. S., Zeidler J. D., Kashyap S., et al. (2021). Evolving concepts in NAD(+) metabolism. Cell Metab. 33:1076−1087. DOI:10.1016/j.cmet.2021.04.003 View in Article CrossRef Google Scholar
[26]	Peng J., Zhang Y., Gao K., et al. (2026). NMN-SIRT1 signaling ameliorates IUGR via oxidative stress-mediated mitophagy to promote placental angiogenesis. Innov. Life 4:100201. DOI:10.59717/j.xinn-life.2026.100201 View in Article CrossRef Google Scholar
[27]	Wu Q. J., Zhang T. N., Chen H. H., et al. (2022). The sirtuin family in health and disease. Signal. Transduct. Target Ther. 7:402. DOI:10.1038/s41392-022-01257-8 View in Article CrossRef Google Scholar
[28]	Zhu Y., Park S. H., Ozden O., et al. (2012). Exploring the electrostatic repulsion model in the role of Sirt3 in directing MnSOD acetylation status and enzymatic activity. Free Radic. Biol. Med. 53:828−833. DOI:10.1016/j.freeradbiomed.2012.06.020 View in Article CrossRef Google Scholar
[29]	Dong Z. B., Wu H. M., He Y. C., et al. (2022). MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1. Cell Death Dis. 13:35. DOI:10.1038/s41419-021-04491-0 View in Article Google Scholar
[30]	Zhao X., Petursson F., Viollet B., et al. (2014). Peroxisome proliferator-activated receptor γ coactivator 1α and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheumatol. 66:3073−3082. DOI:10.1002/art.38791 View in Article CrossRef Google Scholar
[31]	Phang J. M., Liu W. and Zabirnyk O. (2010). Proline metabolism and microenvironmental stress. Annu. Rev. Nutr. 30:441−463. DOI:10.1146/annurev.nutr.012809.104638 View in Article CrossRef Google Scholar
[32]	Huang S., Zhang L., Luo J., et al. (2023). Cysteamine and N-Acetyl-cysteine alleviate placental oxidative stress and barrier function damage induced by deoxynivalenol. J. Agric. Food Chem. 71:6846−6858. DOI:10.1021/acs.jafc.3c00399 View in Article CrossRef Google Scholar
[33]	Gobelli D., Serrano-Lorenzo P., Esteban-Amo M. J., et al. (2023). The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages. iScience 26:107473. DOI:10.1016/j.isci.2023.107473 View in Article CrossRef Google Scholar
[34]	Cao Y., Wang J., Tian H., et al. (2020). Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer. J. Exp. Clin. Cancer Res. 39:119. DOI:10.1186/s13046-020-01621-y View in Article CrossRef Google Scholar
[35]	Jung Y. Y., Ha I. J., Um J. Y., et al. (2022). Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model. J. Adv. Res. 35:245−257. DOI:10.1016/j.jare.2021.03.008 View in Article CrossRef Google Scholar
[36]	Vettore L. A., Westbrook R. L. and Tennant D. A. (2021). Proline metabolism and redox; maintaining a balance in health and disease. Amino acids 53:1779−1788. DOI:10.1007/s00726-021-03051-2 View in Article CrossRef Google Scholar
[37]	Kaul S., Sharma S. S. and Mehta I. K. (2008). Free radical scavenging potential of L-proline: Evidence from in vitro assays. Amino acids 34:315−320. DOI:10.1007/s00726-006-0407-x View in Article CrossRef Google Scholar
[38]	Xiong L., Ye X., Chen Z., et al. (2021). Advanced maternal age-associated SIRT1 deficiency compromises trophoblast epithelial-mesenchymal transition through an increase in vimentin acetylation. Aging cell 20:e13491. DOI:10.1111/acel.13491 View in Article CrossRef Google Scholar
[39]	Bordbari S., Mörchen B., Pylaeva E., et al. (2022). SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of interferon-deficient tumor-associated neutrophils. Int. J. Cancer 150:1198−1211. DOI:10.1002/ijc.33871 View in Article CrossRef Google Scholar
[40]	Alvarez M. E., Savouré A. and Szabados L. (2022). Proline metabolism as regulatory hub. Trends Plant Sci. 27:39−55. DOI:10.1016/j.tplants.2021.07.009 View in Article CrossRef Google Scholar
[41]	Wu G., Bazer F. W., Hu J., et al. (2005). Polyamine synthesis from proline in the developing porcine placenta. Biol. Reprod. 72:842−850. DOI:10.1095/biolreprod.104.036293 View in Article CrossRef Google Scholar
[42]	Liu L., Su X., Quinn W. J., 3rd, et al. (2018). Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27:1067−1080.e1065. DOI:10.1016/j.cmet.2018.03.018 View in Article CrossRef Google Scholar
[43]	Maltepe E. and Fisher S. J. (2015). Placenta: the forgotten organ. Annu. Rev. Cell Dev. Biol. 31:523−552. DOI:10.1146/annurev-cellbio-100814-125620 View in Article CrossRef Google Scholar

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Huang S., Wu D., Chen Z., et al. (2026). Proline-PRODH metabolism promotes placental angiogenesis via the mtROS-STAT3-bFGF/VEGF-A axis. The Innovation Life 4:100233. https://doi.org/10.59717/j.xinn-life.2026.100233

Huang S., Wu D., Chen Z., et al. (2026). Proline-PRODH metabolism promotes placental angiogenesis via the mtROS-STAT3-bFGF/VEGF-A axis. The Innovation Life 4:100233. https://doi.org/10.59717/j.xinn-life.2026.100233

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Proline-PRODH metabolism promotes placental angiogenesis via the mtROS-STAT3-bFGF/VEGF-A axis

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT