Noncanonical role of copper ATPase ATP7B in cadmium detoxification via lysosomal adaptation

Cadmium, a highly toxic metal, disrupts cellular homeostasis by forming stable complexes with thiol‐active proteins, leading to severe liver and lung damage. Despite its toxicity, the mechanisms underlying cadmium export remain poorly understood. Owing to chemical similarity between cadmium and copper, we investigated the role of copper‐exporting ATPases—ATP7A and ATP7B—in cadmium handling. In hepatocytes, cadmium exposure triggers ATP7B trafficking to lysosomes via the retromer complex, accompanied by expansion of acidic lysosomal populations and function. In contrast, ATP7A in lung adenocarcinoma cells undergoes vesicular redistribution without lysosomal sequestration. ATP7B‐deficient hepatocytes display heightened cadmium sensitivity. Lysosomal defective and Cu‐ATPase knockout Caenorhabditis elegans exhibit similar enhanced toxicity, highlighting a noncanonical role of copper ATPase synergised with lysosomal exocytosis pathway in cadmium detoxification.