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Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8\/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis\u2010related proteins (NLRP3, pro\u2010caspase1, caspase1, IL\u20101\u03b2, and Gasdermin D [GSDMD]) as well as autophagy\u2010related proteins (LC3\u2010II, Beclin1, and p62) were examined by Western blotting. The GFP\u2010mRFP\u2010LC3\u2010II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN\u2010induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR\u20108\/SVneo cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results show that hyperglycemia upregulates NLRP3, pro\u2010caspase1, caspase1, IL\u20101\u03b2 at the protein level in GDM patients. High glucose (HG, 25\u2009mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta\u2010gal\u2010positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis\u2010related protein levels of NLRP3, pro\u2010caspase1, caspase1, IL\u20101\u03b2, and GSDMD, Gasdermin D N\u2010terminal domain (GSDMD\u2010N). HG\u2010induced mitochondrial dysfunction and BNIP3 and PINK1\/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3\/PINK1\/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jog.16050","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T23:29:04Z","timestamp":1726615744000},"page":"1813-1829","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>Placental growth factor<\/scp> alleviates hyperglycemia\u2010induced trophoblast pyroptosis by regulating mitophagy"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-176X","authenticated-orcid":false,"given":"Jun","family":"Tao","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College University of South China  Hengyang 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