LRPPRC deficiency drives cuproptosis evasion via metabolic reprogramming and dysregulated copper homeostasis in RCC bone metastasis

Background Bone metastasis poses a significant clinical challenge and remains a major threat to survival in patients with advanced renal cell carcinoma (RCC), and current treatments often fail because metastatic bone lesions are inherently resistant to conventional bone-targeted drugs. Cuproptosis, a recently described copper-dependent form of cell death, has provided new therapeutic insights for cancer treatment. Because cuproptosis depends on mitochondrial metabolism and intracellular copper homeostasis, regulators of mitochondrial mRNA stability may set the threshold for this death modality; however, their role in RCC bone metastasis remains undefined. Methods We compared transcriptomes of 31 RCC bone metastasis samples with 143 primary RCC samples from TCGA, and examined LRPPRC expression in clinical specimens by immunohistochemistry. LRPPRC was then silenced or overexpressed in 786-O and Caki-2 cells, in which cuproptosis sensitivity, FDX1/DLAT expression, mRNA stability, metabolic phenotype and intracellular copper levels were assessed. Finally, LRPPRC-overexpressing 786-O cells were injected intratibially into BALB/c-nu mice to test the combination with elesclomol Cu 2 + . Results LRPPRC was markedly decreased in patients with RCC bone metastasis, and LRPPRC knockdown significantly reduced the expression of FDX1, a key regulator of cuproptosis. Overexpressing LRPPRC combined with elesclomol Cu 2 + notably suppressed tumor progression in both in vitro and in vivo models of bone metastasis. Mechanistically, LRPPRC downregulation promotes tumor cell evasion of cuproptosis through three coordinated mechanisms: (1) it reduces FDX1 mRNA stability, thereby impairing lipoylation; (2) it induces a metabolic shift toward glycolysis, which lowers cellular sensitivity to cuproptosis; and (3) it decreases the stability of SLC31A1 to limit Cu + uptake, while simultaneously reducing the stability of SLC40A1 and STEAP1 to inhibit the conversion of Cu 2 + to Cu + , thus diminishing copper-induced cytotoxicity. Conclusion In summary, this study identified LRPPRC as a central regulator of cuproptosis in RCC. Restoring LRPPRC function combined with elesclomol Cu 2 + therefore represents a promising targeted strategy to overcome the current therapeutic bottleneck in RCC bone metastasis.