High-G (+GZ) exposure is known to induce significant gastrointestinal injury in aviators, yet the underlying mechanisms remain unclear. Ferroptosis is a form of iron-dependent cell death that has been implicated in various pathological conditions, while autophagy plays a critical role in cellular homeostasis and damage regulation. This study investigated the role of autophagy in +Gz-induced intestinal mucosal injury and its interaction with ferroptosis. Sixty female Sprague–Dawley rats were randomly assigned to six groups: control (sham exposure), autophagy inhibition (3-methyladenine, 3-MA), autophagy activation (rapamycin, RAP), +Gz exposure, +Gz exposure with autophagy inhibition, and +Gz exposure with autophagy activation. +Gz exposure was simulated using a small animal centrifuge (+ 10 Gz, 5 min/day for 5 days). Histopathological changes were assessed via haematoxylin–eosin (HE) staining, transmission electron microscopy (TEM), and Chiu scoring. Ferroptosis- and autophagy-related markers (FTH1, NCOA4, GPX4, Nrf2, LC3, and BECN1) were analyzed by Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and immunohistochemistry. Levels of Fe2+ lipid peroxidation (LPO), inflammatory cytokines (tumor necrosis factor-α (TNF-) and interleukin 6 (IL-6) ), and intestinal permeability markers (D-lactate, DAO) were quantified using enzyme-linked immunosorbent assay (ELISA). +Gz exposure led to severe intestinal injury, characterized by villous atrophy, increased Chiu scores, inflammatory infiltration, and mitochondrial structural damage. Ferroptosis was identified as a key pathological mechanism, with elevated Fe2+ level, lipid peroxidation, and downregulation of GPX4 and Nrf2. Autophagy inhibition significantly alleviated intestinal damage, reducing Fe2+ accumulation, ferroptosis markers, and oxidative stress, while restoring Nrf2-GPX4 signaling pathway. Conversely, autophagy activation exacerbated ferroptosis, leading to more severe mitochondrial damage and intestinal dysfunction. This study provided novel evidence that +Gz-induced intestinal injury could be mediated by ferroptosis and regulated by autophagy. Excessive autophagy exacerbates ferroptosis via ferritinophagy-mediated iron release, whereas autophagy inhibition is protective against intestinal damage by preserving the Nrf2-GPX4 axis function. Targeting autophagy and ferroptosis may provide new therapeutic strategies for mitigating high-G-induced gastrointestinal injury in aerospace medicine.
Xu et al. (Fri,) studied this question.