Zixi Wang

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. In this study, 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 cochaperone 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. Significance: A clear-cell renal cell carcinoma risk variant acts as an allele-specific regulatory element that preferentially recruits HOXC8 to repress LINC02068 and promote oxidative phosphorylation, revealing how inherited variation shapes tumor metabolism.

GPX4 overexpression reduces the heightened sensitivity to RSL3 in TRAPPC4 knockdown cells.

TRAPPC4 loss sensitizes HNSCC cells to ferroptosis.

TRAPPC4 regulates ferroptosis resistance of HNSCC cells in vivo.

TRIM55 mediates the effects of TRAPPC4 on ferroptosis sensitivity in HNSCC cells.

TRAPPC4 facilitates HNSCC metastasis through resistance to ferroptosis.

PTV-mediated ferroptosis sensitization is largely dependent on TRAPPC4 in HNSCC cell and xenograft models.

TRAPPC4 knockout suppresses EMT and matrix remodeling associated gene expression.

Overexpression of TRAPPC4 confers resistance to RSL3 induced ferroptosis in PDO models.