MAFB in Pancreatic β-Cell Development and Dysfunction: Implications for Diabetes and Translational Applications

Large MAF transcription factors, including MafA and MafB, are essential for maintaining β-cell identity, function and survival. While MafA has been widely studied in pancreas development and type 2 diabetes, the extended roles of MafB in humans are still emerging. During embryogenesis, MafB promotes differentiation of β-cells. While MafB is downregulated in adult mouse β-cells, it remains active in adult human β-cells, indicating important species-specific functions. Mechanistically, MafB cooperates with other β-cell-specific transcription factors, including PDX1, NEUROD1 and NKX6.1, to regulate genes critical for β-cell differentiation and insulin expression. Loss of MafB in human β-cells is associated with hallmark features of diabetic pathology, such as dedifferentiation, impaired insulin production, and transdifferentiation under metabolic stress. In addition to its endocrine roles within islets, MafB regulates macrophage polarization and apoptotic cell clearance, suggesting immune–metabolic interactions that may contribute to islet inflammation and dysfunction. Translationally, MafB may be leveraged to enhance stem-cell-derived β-cell differentiation and maturation and support β-cell identity preservation under stress and potentially immune responses; however, these applications remain to be further studied and validated. In this review, we integrate findings from developmental biology, animal models, and human studies to clarify the overarching role of MafB in bridging β-cell development, immune regulation, and potential translational application in stem-cell therapy or as a biomarker target in diabetes research.