Proteomic analysis reveals a metabolic switch and cellular remodeling in pancreatic-like cell spheroids cocultured with hepatocyte-like cells using an interconnected liver-pancreas-on-chip system.

Systemic interactions between the liver and pancreas are critical for regulating lipid and carbohydrate homeostasis. These organs are also deeply interdependent in pathological conditions such as insulin resistance, where the liver fails to respond appropriately to insulin stimulation, leading to dysfunction in both organs. To investigate the crosstalk between these tissues using human models, we developed an advanced organ-on-chip (OoC) device hosting human induced pluripotent stem cell (hiPSC)-derived liver and pancreatic tissues. The proteomic response of pancreatic-like cell spheroids cocultured with hepatocyte-like cells was characterized. We observed that the presence of liver tissue enhanced the synthesis of proteins associated with extracellular matrix remodeling, inflammatory responses, and pro-apoptotic signaling in pancreatic cells. Conversely, monocultures of pancreatic cells exhibited higher abundance of proteins involved in fatty acid metabolism, glycolysis, and the citrate cycle. Key pancreatic markers (GCG, TPH1, SCGN3, SCGN, CHGA, CHGB) were upregulated in monocultures, while no reduction was observed in the secretion of pancreatic hormones (IGF2, GHRL, and C-peptide). Overall, our results suggest a metabolic switch in cocultures, accompanied by cellular stress and moderate alterations in pancreatic secretion. These findings provide insights into liver-pancreas crosstalk and may guide the design of future multicellular OoC models.