Malectin Alleviates Endoplasmic Reticulum Stress in Gestational Diabetes Mellitus via Glycoprotein Quality Control Mechanisms.

Gestational diabetes mellitus (GDM), is a prevalent metabolic disorder associated with placental dysfunction and adverse pregnancy outcomes. Emerging evidence points to endoplasmic reticulum (ER) stress as a potential initiating factor in GDM pathogenesis. Moreover, ER stress-mediated trophoblast dysfunction is recognized as a critical pathological mechanism, yet its precise role remains incompletely elucidated. Here, we demonstrate that malectin, an ER-resident lectin, is upregulated in GDM placentas and protects trophoblasts against high glucose (HG)-induced ER stress. Mechanistically, malectin recognizes Glc2-N-glycans on misfolded glycoproteins via six essential carbohydrate-binding residues, thereby facilitating glycoprotein quality control (GQC). Malectin knockdown exacerbated HG-induced 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-N-glycan motifs. Importantly, administration of TAT-Malectin 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-induced ER stress and damage through GQC mediated by its six key carbohydrate-binding 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.