Cadmium targeting the circadian transcription factor BMAL1 to induce osteocyte senescence contributes to osteoporosis

As a ubiquitous environmental pollutant, cadmium (Cd) has been strongly implicated in the development of osteoporosis. However, the cellular and molecular mechanisms mediating its skeletal toxicity remain incompletely understood. Here, we identify osteocytes as a highly vulnerable and previously underrecognized cellular target in Cd-induced osteoporosis. We demonstrate that Cd accumulates in cortical bone and induces pronounced osteocyte senescence in vivo and in vitro. Cd exposure provokes oxidative stress, DNA damage, and cell-cycle arrest in osteocytes, collectively disturbing bone metabolic homeostasis by amplifying senescence signals to neighboring osteoblasts, osteoclasts, and bone marrow stromal cells. Mechanistically, we reveal that brain and muscle ARNT-Like 1 (BMAL1) acts as a pivotal regulator of Cd-induced osteocyte senescence. BMAL1 deficiency exacerbated oxidative stress, senescence, and trabecular and cortical bone deterioration. Conversely, BMAL1 overexpression restored redox balance and markedly attenuated Cd-induced osteocyte senescence. Moreover, eliminating senescent cells using dasatinib plus quercetin markedly reduced osteocyte senescence and improved bone integrity, and co-treatment with melatonin further enhanced these protective effects. These findings reveal an unrecognized osteocyte-centered senescence axis in Cd-induced skeletal toxicity and position BMAL1 as a promising therapeutic target for mitigating pollutant-related bone damage.