Non-B DNA at the Interface of Metabolism, Genome Stability, and Inflammation

DNA most commonly adopts the canonical B-form double helix but can also form alternative conformations, collectively known as non-B DNA structures. These structures, including G-quadruplexes, i-motifs, hairpins, cruciforms, Z-DNA, H-DNA, R-loops, and other repeat-associated structures, have important roles in gene regulation, genome stability, and disease etiology. Emerging evidence suggests that non-B DNA is also involved in metabolic regulation and associated disorders. Here, we discuss how non-B DNA influences the expression of genes involved in insulin regulation, glucose and lipid metabolism, and other metabolic pathways. We also highlight their broader effects on genomic instability, mitochondrial dysfunction, and inflammatory signaling in diabetes, metabolic liver disease, obesity, and related disorders. Importantly, this relationship appears bidirectional, as metabolic and oxidative stress can alter the formation, processing, and stability of non-B DNA structures. Together, these findings position non-B DNA as a potential interface between metabolic stress, gene regulation, and tissue dysfunction.