Dysregulation of the MACF1‐Rab14/KIF16B‐FGFR Vesicular Trafficking Axis Skews MSC Lineage Commitment in Glucocorticoid‐Induced Osteoporosis

ABSTRACT

Glucocorticoid‐induced osteoporosis (GIO) is driven by a pathogenic shift in bone marrow mesenchymal stem cell (BMSC) lineage commitment from osteogenesis to adipogenesis. Here, we identify Microtubule Actin Cross‐linking Factor 1 (MACF1) as a critical regulator of MSC fate that is severely suppressed during long‐term glucocorticoid (GC) exposure. We demonstrate that MACF1 deficiency phenocopies GC‐induced marrow adiposity and bone loss. Crucially, restoring endogenous MACF1 via promoter‐targeted small activating RNA (saRNA) effectively corrects this fate bias and reverses microarchitectural deterioration in GIO mice. Mechanistically, MACF1 acts as a key facilitator of vesicular trafficking. By orchestrating the assembly of the Rab14/KIF16B complex, MACF1 drives the precise anterograde transport of Fibroblast Growth Factor Receptors (FGFRs) to the plasma membrane. GC exposure downregulates MACF1, disrupting this transport machinery and causing intracellular FGFR sequestration. This transport failure depletes functional cell‐surface FGFRs, thereby blunting osteogenic signaling and triggering the adipogenic shift. Collectively, our findings establish the MACF1‐governed intracellular trafficking network as an important determinant of FGFR spatial distribution and MSC fate, highlighting it as a promising therapeutic target for restoring bone‐fat equilibrium in GIO.