Future deep-space missions will expose astronauts to microgravity and ionizing radiation, which induce molecular changes that mirror biological aging, including inflammation, cellular senescence, and fibrotic remodeling. However, the regulatory mechanisms linking spaceflight stressors to aging-associated molecular responses in metabolically important organs such as the liver remain incompletely understood. In this study, we investigated the effects of simulated microgravity and deep-space radiation analogs on microRNA (miRNA) and mRNA networks associated with the transforming growth factor-β (TGF-β) signaling pathway in mouse liver. We further evaluated an antagomir cocktail (miR-16-5p, miR-125b-5p, and let-7a-5p) as a potential countermeasure. Notably, while antagomir treatment influenced genes associated with senescence and inflammatory responses, it increased the expression of fibrosis-associated transcripts. To explore translational relevance, we compared these findings with transcriptomic data from the NASA Twins Study and the Inspiration4 mission. Despite lower radiation exposures, similar regulatory patterns affecting TGF-β-associated genes and miRNAs were observed in human circulating blood cells. Together, these findings suggest that spaceflight-associated stressors perturb hepatic miRNA-TGF-β regulatory networks linked to senescence, inflammation, and fibrotic signaling. Our results support that radiation and microgravity exposures may act as drivers of aging-like molecular responses and highlight miRNA regulatory networks as potential targets for countermeasures during long-duration spaceflight.
