A study on the effects of short-duration spaceflight on human skin using multi-omics approaches reveals significant changes in gene expression, immune responses, and microbial composition. Skin biopsies were collected from the Inspiration4 crew before and after flight, and spatial transcriptomics, single-cell RNA/ATAC-seq, and metagenomics/metatranscriptomics were used to analyze 95 skin regions across four compartments: outer epidermis, inner epidermis, outer dermis, and vasculature. Post-flight samples showed upregulation of genes related to inflammation and KRAS signaling, with changes primarily in outer tissue compartments. These included altered interferon responses, DNA damage, epithelial barrier disruptions, T-cell migration, and hindered regeneration. Epithelial disruption was linked to microbial shifts in skin swabs and immune cell activity in PBMC single-cell data. The study also found changes in skin microbiota, with shifts in bacterial and viral species, and increased abundance of certain microbes like Streptococcus and Veillonella. These changes were associated with skin barrier disruption and immune activation. Additionally, immune changes were observed, including increased T-cell signatures and cytokine levels, suggesting immune-epidermis interactions. The study highlights the importance of KRAS signaling, immune responses, and related pathways in spaceflight-induced skin changes. The findings provide insights into the molecular basis of skin changes during spaceflight and could inform future space missions and countermeasures. The study is limited by a small sample size and short mission duration, but the data was compared with other research and analog models to provide broader context. The results emphasize the need for further research to understand the long-term effects of spaceflight on skin and immune systems.A study on the effects of short-duration spaceflight on human skin using multi-omics approaches reveals significant changes in gene expression, immune responses, and microbial composition. Skin biopsies were collected from the Inspiration4 crew before and after flight, and spatial transcriptomics, single-cell RNA/ATAC-seq, and metagenomics/metatranscriptomics were used to analyze 95 skin regions across four compartments: outer epidermis, inner epidermis, outer dermis, and vasculature. Post-flight samples showed upregulation of genes related to inflammation and KRAS signaling, with changes primarily in outer tissue compartments. These included altered interferon responses, DNA damage, epithelial barrier disruptions, T-cell migration, and hindered regeneration. Epithelial disruption was linked to microbial shifts in skin swabs and immune cell activity in PBMC single-cell data. The study also found changes in skin microbiota, with shifts in bacterial and viral species, and increased abundance of certain microbes like Streptococcus and Veillonella. These changes were associated with skin barrier disruption and immune activation. Additionally, immune changes were observed, including increased T-cell signatures and cytokine levels, suggesting immune-epidermis interactions. The study highlights the importance of KRAS signaling, immune responses, and related pathways in spaceflight-induced skin changes. The findings provide insights into the molecular basis of skin changes during spaceflight and could inform future space missions and countermeasures. The study is limited by a small sample size and short mission duration, but the data was compared with other research and analog models to provide broader context. The results emphasize the need for further research to understand the long-term effects of spaceflight on skin and immune systems.