Abstract
Sepsis can lead to diaphragm dysfunction and atrophy known as sepsis-induced diaphragm dysfunction (SIDD), a major cause of mortality in the ICU. Our present study aimed to investigate whether ferroptosis is implicated in the pathogenesis of SIDD and the underlying molecular mechanism. The results demonstrated that in both in vivo and in vitro septic models, indicators such as the oxygen consumption rate (OCR), extracellular acidification rate (ECAR), reactive oxygen species (ROS), and complex I-V levels, alongside Transmission Electron Microscope (TEM) imaging, revealed mitochondria-associated changes. These alterations were mitigated by the ferroptosis inhibitor Ferrostatin (Fer-1), confirming that ferroptosis—a mitochondria-linked form of programmed cell death, plays a crucial role in SIDD. Through RNA sequencing (RNA-seq), transposase-accessible chromatin sequencing (ATAC-seq), and Dual-Luciferase Reporter Assay, we found that the FOXO3/IL-10 axis was suppressed in septic mice yet can be reactivated through administration of Fer-1. Furthermore, overexpression of FOXO3 shielded the diaphragm against sepsis-induced ferroptosis by boosting IL-10 production and enhancing the expression of Nrf2-mediated antioxidative genes such as GPX4. This reduced lipid peroxidation and concurrently ameliorated mitochondrial damage. Therefore, activating FOXO3 or administering IL-10 could offer a promising approach for treating SIDD.