Multispecies transcriptome analysis identifies networks protecting against MASLD in Göttingen minipigs.

To understand the mechanisms underlying the remarkable resistance of Göttingen minipigs to metabolic dysfunction-associated steatotic liver disease (MASLD), a multilevel transcriptomic analysis comparing their liver with those of humans, mice, and MASLD susceptible pig breeds was performed. This analysis revealed 692 genes uniquely differentially expressed in livers of Göttingen minipigs, linked to multiple metabolic and signaling pathways (e.g., AMPK signaling). Among these, 11 transcription factors (TFs), 3 hepatokines (DPP4, ITIH1, and ITIH3), and 6 additional secreted proteins (including PCSK9 and APOM) exhibited particularly strong differential expression and emerged as candidate mediators of MASLD resistance. This finding was further supported by weighted gene coexpression network analysis, which identified a core regulatory network driven by the TFs HMBOX1 and PATZ1, presumably regulating 41% of its differentially expressed genes. Collectively, these results suggest that a distinct transcriptional program involving HMBOX1/PATZ1 and their downstream targets, including secreted factors, contributes to the MASLD-resistant phenotype of Göttingen minipigs and may provide promising targets for the prevention and treatment of fatty liver disease.