Resveratrol Modulates Bone Metabolism Through SIRT1‐Mediated NF‐κB Inhibition: Molecular Mechanisms and Therapeutic Implications

ABSTRACT

Osteoporosis and associated skeletal pathologies impose a staggering global health burden, disproportionately impacting elderly populations and postmenopausal women. At the root of excessive bone resorption and stalled osteogenesis lie persistent oxidative stress and chronic inflammation. Enter resveratrol, a naturally occurring polyphenol derived from red wine and grapes, which has surfaced as a compelling therapeutic candidate for skeletal preservation owing to its robust antioxidant and anti‐inflammatory capacities. Herein, we evaluate the molecular pathways through which resveratrol governs bone metabolism, focusing sharply on SIRT1‐driven suppression of NF‐κB signaling. Integrating findings across cell cultures, animal models, and clinical trials yields a unified perspective on these osteoprotective mechanisms. Dual benefits define resveratrol's impact on skeletal architecture: it stimulates osteoblast differentiation and mineralization while suppressing osteoclastogenesis and bone resorption. Primarily, these outcomes stem from the activation of SIRT1, a NAD + ‐dependent deacetylase acting as a negative regulator of NF‐κB transcription. Through SIRT1‐mediated deacetylation of the NF‐κB p65 subunit, the transcription of pro‐inflammatory cytokines including IL‐1β, TNF‐α, and IL‐6 diminishes, subsequently dampening RANKL‐driven osteoclastogenesis. Simultaneously, through the SIRT1‐dependent engagement of Nrf2/ARE pathways, antioxidant defenses are bolstered, sparing bone cells from oxidative stress‐induced apoptosis. Substantial preclinical promise notwithstanding, hurdles persist regarding both systemic bioavailability and the standardization of ideal dosing protocols for bone preservation. This review provides a mechanistic framework to evaluate resveratrol as a viable nutraceutical modality for the prevention and management of osteoporosis.