Ocular Risks of Spaceflight and a Path to Prevention: Targeting Mitochondria– ER Stress With Low‐Intensity Ultrasound

The cornea is highly susceptible to spaceflight-induced stress, compromising visual acuity and mission safety. Here, we identify endoplasmic reticulum (ER) and mitochondrial dysfunction as key mediators of corneal degeneration under simulated microgravity (SMG). SMG exposure led to corneal epithelial thinning, reduced nerve fiber density, and delayed wound healing. Multi-omics profiling and cellular assays revealed aberrant ER-mitochondrial crosstalk, characterized by excessive formation of mitochondria-associated membranes (MAMs) and activation of stress signaling pathways. Notably, treatment with low-intensity ultrasound (LIUS) restored corneal epithelial integrity by modulating MAM dynamics, alleviating organelle stress, and normalizing cellular homeostasis. These findings identify a novel molecular axis in microgravity-induced ocular degeneration and propose LIUS as a deployable, non-invasive countermeasure for preserving corneal health during deep spaceflight.