The FOXO1-SIRT1 axis in ankylosing spondylitis: A cross-platform regulator linking immunometabolism, oxidative stress, and bone remodeling

Ankylosing spondylitis (AS) is a chronic immune-mediated disorder defined by the paradoxical coupling of inflammatory bone erosion and ectopic new bone formation. Recent studies implicate the Forkhead box O1 (FOXO1)-Sirtuin 1 (SIRT1) signaling axis as a systems-level regulator integrating immune metabolism, redox balance, and skeletal remodeling. FOXO1 and SIRT1 cooperatively regulate immune tolerance, redox balance, and skeletal homeostasis via transcriptional, epigenetic, and metabolic pathways. This review delineates the cross-platform roles of the FOXO1-SIRT1 axis across three interrelated modules: regulation of immune cell metabolism and polarization; redox sensing and organelle quality control via autophagy and mitophagy; and coordination of osteoblast - osteoclast dynamics in inflammatory microenvironments. Dysregulation of this axis disrupts immuno-metabolic equilibrium and promotes pathological ossification, contributing to the dual pathology of AS. We further discuss emerging therapeutic strategies - ranging from SIRT1 activators and anti -Interleukin-17 A (IL-17 A) biologics to histone deacetylase inhibitors - that converge mechanistically on FOXO1-SIRT1 signaling. These translational approaches underscore the axis's potential as a cross-domain integrator of immune and skeletal homeostasis, and as a promising target for precision intervention in AS.