Sesamin ameliorates high-fat diet-induced inflammation and metabolic dysfunction in pregnant uterine smooth muscle via cGAS-STING inhibition

Background: Maternal obesity and high-fat diets disrupt uterine metabolic homeostasis, leading to mitochondrial dysfunction, Insulin resistance, and inflammation in uterine smooth muscle cells (USMCs), which may compromise pregnancy outcomes. Here, we investigated the role of the cGAS-STING pathway in mediating high-fat-induced metabolic and inflammatory dysfunction in USMCs and evaluated the therapeutic potential of sesamin, a bioactive compound from Cuscuta chinensis.

Methods: Transcriptomic datasets from maternal serum and myometrium were analyzed to identify differentially expressed genes associated with inflammation, Insulin resistance, and cGAS-STING activation. In vitro, USMCs were exposed to palmitic acid to mimic a high-fat environment, and mitochondrial integrity, mtDNA release, cGAS-STING activation, Insulin signaling, and glucose uptake were assessed using TEM, ROS and JC-1 staining, qRT-PCR, Western blotting, and ELISA. In vivo, pregnant C57BL/6 mice were fed either a high-fat diet (HFD) or normal diet, with or without oral sesamin administration, and metabolic, mitochondrial, and inflammatory parameters were evaluated.

Results: High-fat exposure induced mitochondrial structural damage, ROS accumulation, and mtDNA leakage, which activated cGAS-STING signaling and upregulated pro-inflammatory cytokines (IL-1β, IL-18), impairing Insulin signaling in USMCs. Selective mtDNA depletion or STING knockdown attenuated these effects. Sesamin bound STING with high affinity, inhibited cGAS-STING activation, restored Insulin signaling, improved glucose uptake, and enhanced mitochondrial respiratory function. In HFD mice, sesamin reduced systemic inflammation, improved uterine Insulin sensitivity, and normalized metabolic rates (VO₂, VCO₂, and RER).

Conclusion: These findings demonstrate that high-fat-induced cGAS-STING activation underlies mitochondrial dysfunction, inflammation, and Insulin resistance in USMCs. Sesamin mitigates these effects via dual regulation of STING signaling and mitochondrial function, highlighting its potential as a therapeutic agent for metabolic and inflammatory dysregulation in pregnancy.