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Emerging evidence points to endoplasmic reticulum (ER) stress as a potential initiating factor in GDM pathogenesis. Moreover, ER stress\u2010mediated trophoblast dysfunction is recognized as a critical pathological mechanism, yet its precise role remains incompletely elucidated. Here, we demonstrate that malectin, an ER\u2010resident lectin, is upregulated in GDM placentas and protects trophoblasts against high glucose (HG)\u2010induced ER stress. Mechanistically, malectin recognizes Glc2\u2010N\u2010glycans on misfolded glycoproteins via six essential carbohydrate\u2010binding residues, thereby facilitating glycoprotein quality control (GQC). Malectin knockdown exacerbated HG\u2010induced ER stress, apoptosis, and impaired trophoblast invasion, syncytialization, and glucose uptake, whereas its overexpression attenuated these defects. Structural analyses revealed the molecular basis for malectin's specificity toward Glc2\u2010N\u2010glycan motifs. Importantly, administration of TAT\u2010Malectin ameliorated hyperglycemia and placental ER stress in a GDM mouse model. In summary, our study provides the first evidence that malectin protects placental trophoblasts from HG\u2010induced ER stress and damage through GQC mediated by its six key carbohydrate\u2010binding residues. These findings establish malectin as both a key endogenous placental protector and a promising protein therapeutic candidate, offering a novel target and therapeutic strategy for GDM.<\/jats:p>","DOI":"10.1002\/advs.202508901","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T14:46:01Z","timestamp":1779720361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Malectin Alleviates Endoplasmic Reticulum Stress in Gestational Diabetes Mellitus via Glycoprotein Quality Control Mechanisms"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiahui","family":"Zhu","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Brain Disease Bioinformation Research Center for Biochemistry and Molecular Biology Xuzhou Medical University  Xuzhou China"},{"name":"National Experimental Demonstration Center for Basic Medicine Education Xuzhou Medical University  Xuzhou 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