DOTMP induces nephrotoxicity via the Hsp90β/PI3K signaling axis.

Bone metastasis frequently occurs in advanced malignancies and is often accompanied by skeletal-related events such as intractable pain and pathological fractures, severely compromising patients' quality of life. Targeted radionuclide theranostics currently serves as a crucial clinical modality for managing such conditions; however, the dose-limiting nephrotoxicity induced during treatment severely limits its clinical therapeutic window. As a clinical bone-targeting polyphosphonate chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP) exhibits excellent targeting efficacy in the theranostics of bone metastases. Nevertheless, due to its primary excretion via the kidneys, it is selectively taken up by renal tubular epithelial cells, thereby triggering significant renal injury. Given that the core targets and molecular networks underlying DOTMP-induced nephrotoxicity remain to be fully elucidated, this study aims to decipher its toxicological mechanisms from a systems biology perspective. Network toxicology and topological analyses identified HSP90AB1, PIK3CA, SRC, and MTOR as candidate hub genes potentially associated with DOTMP-related renal injury. Molecular docking predicted that Hsp90β had the most favorable docking score among the evaluated targets. A single 100-ns MD trajectory further supported the stability of the predicted DOTMP-Hsp90β binding pose. CETSA indicated DOTMP-associated thermal stabilization of endogenous Hsp90β. This study suggests that DOTMP-induced renal cell injury is associated with Hsp90β-related PI3K signaling. Computational prediction and CETSA supported a potential interaction between DOTMP and Hsp90β. DOTMP suppressed Hsp90β expression and PI3K/Src/mTOR-related phosphorylation and promoted apoptosis in renal cells. These findings provide insight into the potential nephrotoxicity of DOTMP and may inform the safety evaluation of bone-targeting radiopharmaceuticals.