A germline-encoded lncRNA-mitochondrial axis rewires oxidative phosphorylation and therapeutic susceptibility in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) exhibits profound metabolic reprogramming and substantial inherited susceptibility, yet how genetic determinants mechanistically shape tumor metabolism and therapeutic vulnerability remains poorly defined. Here, we integrate whole-genome sequencing and transcriptomic profiling of matched tumor and normal kidney tissues from a large ccRCC cohort with cross-ancestry genome-wide association, cis-expression quantitative trait locus, and transcriptome-wide association analyses to systematically define the germline regulatory landscape of renal cancer. We identify the long noncoding RNA LINC02068 as a genetically-regulated tumor suppressor whose repression mediates inherited ccRCC risk. The risk variant rs234043 functions as an allele-specific silencer by preferentially recruiting the transcription factor HOXC8, leading to transcriptional repression of LINC02068. Loss of LINC02068 promotes aggressive tumor phenotypes and is associated with adverse clinical outcomes. Mechanistically, LINC02068 localizes to mitochondria and directly interacts with the co-chaperone DNAJA3, accelerating its destabilization and thereby constraining mitochondrial oxidative phosphorylation. Allele-specific genome editing, genetic rescue, and metabolic profiling support a functionalrs234043-HOXC8-LINC02068-DNAJA3 regulatory axis that links inherited genetic variation tomitochondrial activity and tumor progression. Pharmacologic inhibition of mitochondrial complex I by MitoTam suppresses ccRCC cell migration and proliferative growth, further supporting complex I-linked mitochondrial respiration as a functional metabolic dependency in ccRCC. Collectively, these findings uncover a germline-encoded metabolic checkpoint linking noncoding genetic variation to mitochondrial regulation, tumor aggressiveness in ccRCC, providing a mechanistic rationale for exploring mitochondria-targeted therapeutic strategies.