The liver is a central metabolic hub, performing vital functions such as bile production, protein, carbohydrate, lipid and drug metabolism, detoxification of xenobiotics, and the synthesis of essential biomolecules for reproduction, and also shows regenerative capability. Several of these functions can be affected by sexual dimorphisms with important consequences. In this study we used high-throughput proteomics to identify and quantify proteins involved in sexual dimorphism of the zebrafish liver, as a model for preclinical human research. Additionally, we conducted an extensive literature review to explore potential effects of sex-biased protein abundances on liver regeneration capacity and hepatic diseases. The results showed wide-spread sex-specific differences in proteins involved in carbohydrate, protein, and lipid metabolism. Female livers exhibited higher levels of proteins involved in protein synthesis, while male liver protein abundances were higher in energy-producing biochemical pathways, such as the TCA, β-oxidation, and glycolysis. Furthermore, significant sex differences were observed in proteins related to drug metabolism, which should be considered in toxicological and pharmacological research. Some potential links between sex-biased quantities of some key hepatic proteins and the susceptibility of males to liver diseases, as well as the higher hepatic regenerative capacity in females, were suggested. These findings offer a foundation for future targeted research to facilitate the development of sex-specific therapeutic approaches for liver disorders and regenerative medicine. Data are available via ProteomeXchange with identifier PXD061886.

Department of Immunotechnology Science for Life Laboratory Lund University Lund Sweden

Faculty of Fisheries and Protection of Waters University of South Bohemia in České Budějovice CENAKVA Zátiší 728 2 38925 Vodňany Czech Republic

School of Ecology Sun Yat sen University Shenzhen China

School of Fisheries Aquaculture and Aquatic Sciences Auburn University Alabama USA

Science for Life Laboratory National Bioinformatics Infrastructure Sweden Lund University Lund Sweden

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