Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway

Objective Gestational diabetes mellitus (GDM) is associated with gut microbiota dysbiosis and placental dysfunction. This study aimed to investigate whether gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate placental injury and insulin resistance in GDM by suppressing ferroptosis, a novel form of iron-dependent cell death. Methods A GDM rat model was induced by streptozotocin, and gut microbiota was depleted via a broad-spectrum antibiotic cocktail. Physiological parameters, gut microbiota composition, and SCFA levels were assessed. Placental and metabolic tissues were analyzed for ferroptosis markers (Fe 2+ , MDA, ROS), key regulatory enzymes (GPX4, ACSL4, LPCAT3), polyunsaturated fatty acid (PUFA) profiles, and inflammation. An in vitro insulin resistance model in human trophoblast cells (HTR-8/SVneo) was used to validate the causal role of SCFAs. Results GDM and antibiotic-induced dysbiosis led to a significant depletion of SCFA-producing bacteria and reduced colonic SCFA levels. This was concomitant with severe placental ferroptosis, characterized by iron accumulation, lipid peroxidation, and downregulation of GPX4 alongside upregulation of ACSL4 and LPCAT3. PUFA substrates were significantly consumed, and systemic inflammation was elevated. In vitro , insulin resistance induced trophoblast ferroptosis and dysfunction, which was effectively rescued by SCFA treatment. SCFAs restored GPX4 expression, suppressed ACSL4/LPCAT3, preserved PUFAs, and attenuated inflammation. Conclusion Gut microbiota-derived SCFAs play a critical protective role in GDM by inhibiting the ACSL4/LPCAT3-mediated ferroptotic pathway in placental trophoblasts, thereby improving insulin sensitivity and mitigating cellular injury. Our findings highlight the gut-placenta axis as a potential therapeutic target for GDM, warranting further validation in human studies.