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Social interactions affect physiological and pathological processes, yet their direct impact in peripheral tissues remains elusive. Recently we showed that disruption of pair bonds in monogamous Peromyscus californicus promotes lung tumorigenesis, pointing to a direct effect of bonding status in the periphery (Naderi et al., 2021). Here we show that lung transcriptomes of tumor-free Peromyscus are altered in a manner that depends on pair bonding and superseding the impact of genetic relevance between siblings. Pathways affected involve response to hypoxia and heart development. These effects are consistent with the profile of the serum proteome of bonded and bond-disrupted Peromyscus and were extended to lung cancer cells cultured in vitro, with sera from animals that differ in bonding experiences. In this setting, the species' origin of serum (deer mouse vs FBS) is the most potent discriminator of RNA expression profiles, followed by bonding status. By analyzing the transcriptomes of lung cancer cells exposed to deer mouse sera, an expression signature was developed that discriminates cells according to the history of social interactions and possesses prognostic significance when applied to primary human lung cancers. The results suggest that present and past social experiences modulate the expression profile of peripheral tissues such as the lungs, in a manner that impacts physiological processes and may affect disease outcomes. Furthermore, they show that besides the direct effects of the hormones that regulate bonding behavior, physiological changes influencing oxygen metabolism may contribute to the adverse effects of bond disruption., (© 2023. The Author(s).)