This study will provide insight into the mechanism whereby PQQ inhibits oxidative stress and prevents age‐related osteoporosis by indirectly inhibiting osteoclastic bone resorption via MCM3‐Keap1‐Nrf2 signaling activation in osteoblast‐lineage cells and provides evidence for PQQ as an attractive agent for the prevention and treatment of natural aging‐induced osteoporosis. The gene discussed is KEAP1; the disease is osteoporosis.