Potential modulation of ED-71 in regulating H3K18 histone lactylation to suppress osteoclast differentiation and alleviate postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is primarily characterized by excessive osteoclast activation. This study aimed to explore whether estrogen deficiency regulates osteoclast function through metabolic and epigenetic mechanisms and to elucidate the interventional effects of the novel active vitamin D analog eldecalcitol (ED-71). Using an ovariectomized (OVX) rat model and in vitro experiments, we showed that estrogen deficiency enhances glycolysis in osteoclasts, leading to lactate accumulation and increased levels of histone H3K18 lactylation (H3K18la), which subsequently induces endoplasmic reticulum (ER) dysfunction. The ER dysfunction further promotes hyperactivation of the store-operated calcium entry (SOCE) pathway, ultimately driving excessive osteoclast differentiation and bone resorption. This study demonstrated an associated "metabolism-epigenetics-calcium signaling" axis in osteoclasts under estrogen-deficient conditions. Furthermore, we demonstrated that ED-71 treatment effectively disrupts this regulatory axis by suppressing glycolysis, reducing H3K18la levels, and alleviating ER stress, inhibiting SOCE and restoring bone homeostasis. Our findings provide novel insights into the pathogenesis of PMOP and establish ED-71 as a promising multi-target therapeutic agent.