Female transcriptomic responses to simulated microgravity in a dry immersion model: insights into TP53-regulated stress pathway

Dry immersion (DI) serves as a validated analogue for microgravity, yet transcriptomic responses in women have been scarcely studied. Here, we present a TP53-focused transcriptomics re-analysis of female participants following 5 days of DI, highlighting TP53-related stress responses relevant to astronaut health. RNA-seq data were generated from blood samples collected from 18 healthy women at baseline (BDC-1), day 2 (DI2), day 5 (DI5), and post-recovery (R + 1). Differential gene expression and pathway enrichment analyses assessed timepoint-specific transcriptional changes, with emphasis on TP53 regulation. Principal component analysis showed timepoint-dependent divergence, with the most significant alterations occurring at DI5 and a partial reversion by R + 1. TP53 targets linked to DNA repair ( GADD45A, DDB2 ), oxidative defence ( SESN1, TP53I3 ), and apoptosis ( BAX, BBC3 ) were upregulated during immersion. Pathway responses included activation of hypoxia and interferon signalling, and suppression of haem metabolism and coagulation. Together, these findings provide insight into female molecular adaptation to short-term unloading, highlighting a swift yet reversible TP53 response accompanied by immune, metabolic, and vascular adaptations. These observations advance our understanding of the molecular mechanisms underlying women’s physiological responses to unloading and support the development of sex-informed precision health strategies for future space missions.