Trans-zeatin suppresses osteoclastogenesis and prevents estrogen deficiency-induced bone loss by modulating Nrf2-mediated redox homeostasis and AKT signaling.

Postmenopausal osteoporosis (PMOP) is a metabolic bone disorder driven by excessive osteoclast (OC) activity, but current therapies are limited by adverse effects. Trans-zeatin (TZ), a naturally occurring plant cytokinin with antioxidant properties, has not been investigated in bone metabolism. Here, we show that TZ suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption in vitro and attenuates ovariectomy-induced trabecular bone loss in mice. Mechanistically, TZ activates nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses by upregulating heme oxygenase-1 (HO-1) and catalase while suppressing NADPH oxidase 4 (NOX4) expression, thereby reducing reactive oxygen species (ROS) accumulation. This redox modulation subsequently dampens protein kinase B (AKT) signaling, downregulates the c-Fos/nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) transcriptional program, and decreases the expression of OC-specific effector genes. Notably, Nrf2 knockdown partially reverses the inhibitory effects of TZ, whereas concurrent AKT knockdown attenuates this rescue effect, suggesting that AKT is an important downstream signaling component associated with Nrf2-mediated redox regulation. Collectively, these findings identify TZ as a promising natural candidate for PMOP intervention through coordinated regulation of redox homeostasis and AKT-dependent osteoclastogenic signaling.