BACH1/HO-1 axis dysregulation links Down syndrome to Alzheimer-like neurodegeneration.

Down syndrome (DS), caused by trisomy of chromosome 21, is characterized by early-onset oxidative stress, impaired neuronal development, and an increased risk of Alzheimer's disease (AD)-like neuropathology. Among chromosome 21 genes, the transcription factor BTB and CNC homology 1 (BACH1) has emerged as a critical regulator of redox homeostasis. Under physiological conditions, the balance between BACH1 and nuclear factor erythroid 2-related factor 2 (NRF2) warrants tight control of antioxidant defenses and heme metabolism. However, in DS, BACH1 overexpression disrupts this balance, impairing the induction of heme oxygenase-1 (HO-1) and of other cytoprotective pathways, thereby contributing to chronic oxidative stress, neuronal vulnerability, and pathological processes. The present review summarizes the molecular mechanisms that regulate the BACH1/HO-1 axis in the central nervous system. We recapitulate data from studies showing how dysregulation of this axis affects antioxidant defenses, iron homeostasis, ferroptosis, neuroinflammation, and mitochondrial function. We further provide evidence from the aging and AD literature, highlighting BACH1 as a convergent molecular node linking genetic and age-related neurodegeneration. Remarkably, we explore BACH1's contribution to the transition of DS to AD-like pathology. Finally, we evaluate emerging therapeutic strategies employing BACH1 inhibitors, NRF2 activators, and upstream signaling pathway modulators, and assess their applicability to the AD-like dementia context, concluding that targeting BACH1-dependent regulation of HO-1 represents a promising and unifying strategy to mitigate neurodegeneration in both DS and AD.