From Collapse to Active Self‐Repair: Integrative Multi‐Omics and Machine Learning Analysis Map the Hepatic Metabolic Adaption in Response to Simulated Spaceflight Stress

Long-term spaceflight poses substantial challenges to human physiology, with the liver being highly susceptible due to its central metabolic role. To determine whether hepatic alterations represent transient stress or sustained remodeling, we performed an integrated multi-omics analysis in a rat model simulating chronic space radiation and microgravity. Herein, we applied an integrated multi-omics and AI-driven analytical framework combining histopathology, cytokine and miRNA profiling, proteomics, metabolomics and Western blot validation. After 21 days of simulated space conditions, rats exhibited significant hepatic atrophy, histopathological injury, and metabolic dysfunction resembling a NAFLD-like phenotype, accompanied by multi-omics signatures of impaired oxidative phosphorylation, disrupted TCA cycle activity, altered lipid-metabolic regulation, and inflammatory remodeling. During a 14-day recovery phase, hepatic atrophy and histological lesions were incompletely improved, with omics changes suggesting partial restoration of mitochondrial related energy metabolism, PPAR associated lipid regulation, and fatty acid β-oxidation. Machine learning-based proteomics identified a panel of energy-related and lipid-metabolic proteins that robustly distinguished injury from recovery states. External validation with NASA GeneLab transcriptomic datasets supported the suppression of extracellular matrix programs and structural repair during injury. Together, these findings organize the hepatic response to simulated spaceflight into (1) AMPK/PPAR-γ/PGC-1α-centered energy-related lipid/mitochondrial regulation, (2) ACSM5/CRAT-associated fatty-acid utilization and carnitine-shuttle remodeling, and (3) TGF-β/IGF1-related structural repair and anabolic signaling. This study provides a comprehensive organ-level overview for understanding hepatic adaptation to extreme spaceflight environments and identifies potential targets for mitigating astronaut health risks during long-duration missions.