This research intends to explore the molecular mechanism by which Zn alleviates septic AKI in pregnant mice, with a focus on the gut-kidney axis. A septic AKI model was established in non-pregnant and pregnant mice using the cecal ligation and puncture (CLP) method. The changes in serum Zn over time after modeling were observed. Mice were administered with varying doses (low, medium, and high) of zinc gluconate via gavage, subjected to MTF1 knockdown or overexpression, or treated with the PINK1 activator PARL-IN-2, the autophagy inhibitor chloroquine, or the ferroptosis inhibitor Ferrostatin-1. Following these interventions, pathological changes in kidney and intestinal tissues, intestinal barrier function, abundance of specific gut microbiota, and mitophagy and ferroptosis in kidney tissues were assessed accordingly. In CLP-induced septic pregnant mice, serum Zn was depleted. These changes coincided with significant pathological changes in kidney tissue, the intestinal barrier disruption, dysbiosis of the specific gut microbiota, repressed mitophagy, and enhanced ferroptosis. Zn treatment partially ameliorated the kidney injury, activated the MTF1/Nrf2 pathway, restored intestinal barrier function and specific gut microbiota abundance, activated PINK1/Parkin and mitophagy, and restrained ferroptosis. Mechanistic experiments validated that Zn could activate the MTF1/Nrf2 axis, restore the balance of specific gut microbiota abundance, and activate PINK1/Parkin/mitophagy through the gut-kidney axis to alleviate ferroptosis and ameliorate septic AKI in pregnant mice. Zinc ameliorates sepsis-induced AKI in pregnant mice by activating PINK1/Parkin-mediated mitophagy through the MTF1/Nrf2-gut-kidney axis, thereby alleviating ferroptosis and preserving kidney function.
