A Germline-Encoded lncRNA-Mitochondrial Axis Rewires Oxidative Phosphorylation to Drive Progression in Clear Cell...

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic reprogramming and substantial inherited susceptibility. The molecular mechanisms linking germline risk variation to tumor metabolic reprogramming could potentially be exploited for precision interventions. Here, we aimed to delineate the germline regulatory architecture underlying ccRCC susceptibility and to determine how inherited noncoding variation influences mitochondrial metabolism and tumor progression. Whole-genome sequencing and transcriptomic profiling of matched ccRCC tumor and adjacent normal kidney tissues were integrated with cross-ancestry genome-wide association, cis-expression quantitative trait locus, transcriptome-wide association, and fine-mapping analyses. LINC02068 was identified as a genetically regulated tumor suppressor associated with inherited ccRCC susceptibility, and cross-ancestry fine-mapping prioritized rs234043 as a candidate causal variant. The rs234043 risk allele preferentially recruited HOXC8 and repressed LINC02068 transcription. Reduced LINC02068 expression promoted malignant cellular phenotypes and was associated with adverse clinical outcomes. Mechanistically, LINC02068 localized to mitochondria, interacted with the co-chaperone DNAJA3, and promoted DNAJA3 destabilization, thereby attenuating mitochondrial oxidative phosphorylation. Allele-specific editing and genetic rescue experiments further supported a functional rs234043-HOXC8-LINC02068-DNAJA3 regulatory axis driving ccRCC progression. Pharmacologic impairment of mitochondrial complex I suppressed ccRCC cell migration and proliferation. These findings establish a mechanistic link between a germline noncoding variation and mitochondrial metabolic reprogramming in ccRCC and identify targeting oxidative phosphorylation as a potential avenue for precision therapy.