FABP4 as a critical mediator in osteoporosis: inhibition strategies and therapeutic potential

Fatty acid-binding protein 4 (FABP4), a key lipid protein in metabolism and inflammation, has been suggested to be linked to osteoporosis (OP), though direct evidence is scarce. Here, we present the first clear evidence of FABP4's significant role in OP, supported by clinical data and comprehensive in vivo and in vitro experiments. Elevated serum FABP4 in OP patients inversely correlates with bone mineral density (BMD), with similar trends observed in OVX mice. While FABP4 does not influence osteoblast differentiation, it promotes osteoclast formation and bone resorption. The FABP4 inhibitor BMS309403, with an IC ₅₀ of 0.89 µM, inhibits osteoclast differentiation by modulating calcium ions and suppressing the Ca ²⁺ -Calcineurin-NFATc pathway. Oral BMS309403 increased BMD in OVX mice, albeit less effectively than alendronate, whereas bone-targeted PLGA nanoparticles showed comparable efficacy to alendronate. This research identifies FABP4 as a promising therapeutic target for OP, with significant clinical implications.