Honokiol, a structurally defined natural product, promotes SIRT3-linked bone formation in osteoporotic bone remodeling and fracture repair

CONTEXT: Honokiol is a structurally defined biphenolic natural product with reported mitochondrial and cytoprotective activities. Whether honokiol modifies pathological skeletal remodeling through sirtuin 3 (SIRT3)-linked mechanisms remains unclear. OBJECTIVE: This study investigated whether honokiol regulates bone cell lineage responses and improves osteoporotic bone remodeling and fracture repair through SIRT3-associated bone formation. MATERIALS AND METHODS: effects were examined in ovariectomized mice and stabilized femoral fracture models. Local AAV-shSIRT3 delivery was used to evaluate target dependence. Outcomes included micro-computed tomography, histology, osteocalcin immunohistochemistry, calcein double labeling, and three-point bending analysis. RESULTS: Recombinant SIRT3 enhanced osteogenic mineralization and suppressed adipogenic differentiation and osteoclastogenesis. Honokiol increased SIRT3 expression and produced a similar lineage-shifting profile. SIRT3 knockdown markedly attenuated honokiol-induced osteogenesis, whereas its anti-adipogenic and anti-osteoclastogenic effects were only partly reduced. In ovariectomized mice, honokiol improved trabecular microarchitecture, mineral apposition, osteoblast activity, and femoral strength while reducing marrow adiposity and osteoclast burden. In fractured femora, honokiol increased mineralized callus formation, osteoblast activity, and biomechanical recovery. Local AAV-shSIRT3 intervention weakened these benefits, particularly for bone-forming and structural endpoints. DISCUSSION AND CONCLUSION: Honokiol demonstrates a preclinical skeletal pharmacological profile characterized by predominantly SIRT3-linked bone formation. Its broader effects on adipogenic and osteoclast-associated responses appear only partly SIRT3-dependent.