Bone Marrow Macrophage STING Signaling is a Direct Nexus Linking Marrow Adipose Expansion to NAD + Depletion and Osteogenic Decline in Skeletal Aging

ABSTRACT Reversing the destructive remodeling of the bone marrow microenvironment during aging remains a major challenge. Here, we reveal an age‐dependent dual role of bone marrow macrophage (BMM) STING signaling during skeletal aging. While BMM STING deficiency is detrimental during early bone development and maturation, it paradoxically confers protection against age‐related bone loss from middle age onward. Mechanistically, accumulating bone marrow adipocytes secrete substantial soluble dipeptidyl peptidase 4 (sDPP4). This sDPP4 functions as an extracellular ligand for Toll‐like receptor 4 on BMMs, thereby collaborating with endogenous mitochondrial DNA to activate STING signaling. This STING activation concurrently induces a CD38‐dependent salvage synthesis pathway. Importantly, this STING‐driven upregulation of CD38 not only amplifies bone marrow inflammation but also, through its ecto‐nicotinamide adenine dinucleotide (NAD + ) activity, depletes the precursor nicotinamide mononucleotide (NMN) required for NAD + salvage synthesis, thereby impairing NMN availability and osteogenic capacity in neighboring bone marrow mesenchymal stem cells. Finally, therapeutic intervention combining STING pharmacological inhibition with NMN supplementation effectively attenuated bone loss in preclinical models. Thus, we propose BMM STING signaling as a direct nexus connecting marrow adipose accumulation, innate immune inflammation, and diminished bone formation, and emphasize its targeting potential for managing the aged bone marrow microenvironment.