BACH transcription factors in diseases of the exocrine and endocrine pancreas: effects, mechanisms, and clinical implications

The BTB and CNC homology (BACH) proteins BACH1 and BACH2 are highly conserved transcriptional repressors that exert their effects by forming heterodimers with small musculoaponeurotic fibrosarcoma (MAF) proteins. BACH1 is ubiquitously expressed and functions by competing with nuclear factor erythroid 2-like 2 (NRF2) for binding to MAF. By suppressing the transcription of heme oxygenase 1 ( HO-1 / HMOX1 ), BACH1 inhibits the expression of genes involved in cellular oxidative stress responses. Expression of BACH2 is largely restricted to immune cells in both innate and adaptive compartments, where it plays a central role in hematopoietic development and immune cell differentiation. By engaging stretch or super-enhancers, BACH2 targets gene networks that include cytokines and cytokine receptors. Both BACH proteins have been implicated in numerous chronic diseases, including cancer and immune-mediated chronic inflammatory diseases. Aberrant activation is a key driver of BACH1-related pathogenesis, whereas BACH2 is typically linked to loss-of-function alterations. This article reviews the role of BACH proteins in diseases of the endocrine and exocrine pancreas, with a focus on type 1 and 2 diabetes mellitus, pancreatitis, and pancreatic cancer. Mechanistic aspects, pathophysiological correlations, and potential avenues for targeted therapies are discussed.