Xiphias gladius is an important fishing resource. The Mediterranean stock is affected by overfishing and is declining. In this light, the aim of this study was to evaluate the cross-talk among metabolism, stress response, immune system and reproduction in immature and mature females, coupling histological and transcriptomic approaches. The transcriptome of livers from 3 immature and 3 mature females was analyzed using the Artificial Intelligence RNA-Seq. For the histological analysis, ovary and liver samples were collected from 50 specimens caught during the reproductive season in the Mediterranean Sea. A total of 750 genes were differentially expressed between the livers. The gene ontologtabey analysis showed 91 upregulated and 161 downregulated biological process GO terms. Instead, the KEGG enrichment analysis revealed 15 enriched pathways. Furthermore, the binding occurring between estrogen receptors and aryl hydrocarbon receptor nuclear translocator, upregulated in mature females, could be liable for the inhibition of detoxification pathway. Indeed, at the histological level, mature females showed a higher density and number of melanomacrophage centers, biomarkers of stress. The present findings reveal the cross-talk among response to environmental stressors, metabolism and reproduction, highlighting that mature females invest a lot of energy in reproduction instead of immune response and detoxification.