Fructose-1,6-bisphosphatase as a therapeutic target for type 2 diabetes: from molecular mechanisms to clinical translation.

Type 2 diabetes mellitus (T2DM) affects over 415 million individuals globally, with excessive hepatic glucose production representing a primary contributor to hyperglycaemia. Fructose-1,6-bisphosphatase (FBP1), a rate-limiting gluconeogenic enzyme, has emerged as a promising therapeutic target. This review examines FBP1's molecular mechanisms, including its tetrameric structure and allosteric regulation by AMP. FBP1 dysregulation in diabetes involves transcriptional control by FOXO1, CREB, PGC-1α, and epigenetic modifications. Drug discovery efforts have yielded diverse inhibitor classes, including AMP-competitive inhibitors, covalent modulators targeting cysteines C128/C179, and natural products. Leading compounds demonstrate exceptional potency (IC50 0.029 μM) with favourable bioavailability and efficacy in preclinical models. Structure-based design and AI-driven approaches have accelerated optimisation. Clinical translation of FBP1 inhibitors represents a paradigm-shifting opportunity, potentially providing the first medication class specifically targeting hepatic gluconeogenesis for T2DM treatment.