Ceruloplasmin deficiency promotes osteoclast cuproptosis-like cell death and is associated with higher bone mass in OVX mice with coordinated activation of AMPK/p53 signaling

Abstract Osteoclast bone resorption consumes a large amount of energy, and its energy metabolism disorder is an important pathogenesis of bone metabolism diseases such as osteoporosis. Excessive copper ions interfere with the energy metabolism of the mitochondrial tricarboxylic acid cycle, leading to cuproptosis—a recently identified form of regulated cell death. Ceruloplasmin (CP), a major copper-binding protein, is associated with osteoporosis. However, the role and mechanism of CP in regulating osteoclast energy metabolism in association with osteoclast cuproptosis remain unclear. Our research found that CP inhibited elesclomol-copper (ES-Cu)-induced osteoclast cuproptosis-like cell death, thereby promoting osteoclast formation and overall bone resorption. CP downregulated the expression of cuproptosis-related genes ( Lipt1 , Gls , Pdhb , Fdx1 , Dlat , and Pdha1 ) in osteoclasts. In vivo, CP deficiency preserved higher bone mass in OVX mice at the macroscopic tissue level. Mechanistically, CP suppressed ES-Cu-induced AMPK/p53 pathway activation during osteoclastogenesis. Notably, the direct causal relationship between AMPK/p53 signaling and CP-modulated osteoclast cuproptosis has not been definitively established in this study, and the observed regulatory correlation requires further rigorous functional verification. Targeting CP may represent a potential therapeutic strategy for postmenopausal osteoporosis by inducing osteoclast cuproptosis.