MODY Mutations in Transcription Factors <i>HNF1A</i> and <i>HNF1B</i> Affect the Production of Interferon Signaling Proteins: Evidence at the Proteome Level

ABSTRACT This discovery study investigated the impact of MODY‐associated mutations in hepatocyte nuclear factors HNF1A and HNF1B on the cellular proteome, aiming to identify affected pathways and advance understanding of diabetes pathogenesis. Human induced pluripotent stem cells (hiPSCs) carrying the HNF1A frameshift mutation (p.Pro291fsinsC) were differentiated into pancreatic progenitors, and renal proximal tubule epithelial cells (RPTECs) were engineered to overexpress HNF1B with the S148L point mutation. Label‐free quantitative proteomics was performed using data‐dependent and data‐independent acquisition on Orbitrap and timsTOF mass spectrometers. Pathway enrichment was analyzed using Qiagen IPA, Hallmark gene sets, and STRING networks. Comprehensive proteome coverage (over 7000 proteins) revealed consistent downregulation of oxidative phosphorylation, mitochondrial function, and interferon signaling pathways. Both models exhibited suppression of innate immune responses, with overlapping downregulated proteins, including members of the OAS, IFIT, and MX1 families. Using label‐free proteomics, we show that MODY‐associated mutations in HNF1A and HNF1B suppress mitochondrial function and interferon signaling and are additionally associated with reduced abundance of predicted targets such as A1CF as well as diabetes‐related proteins including SCGN, supporting their role in diabetes pathogenesis.