TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway

Papillary renal cell carcinoma (pRCC) is a challenging renal cell carcinoma subtype with poor prognosis and limited treatment options due to the lack of reliable biomarkers. The tripartite motif (TRIM) protein family is involved in various cellular processes, including oncogenesis. Among these, TRIM59 has emerged as a potential oncogene in multiple cancers; however, its role in pRCC progression remains unclear. Here, by using RNA sequencing data from The Cancer Genome Atlas (TCGA) and LASSO Cox regression analysis, we developed a prognostic model based on TRIM family genes for pRCC, with RiskScore demonstrating potential as a prognostic biomarker. Through the comparison of overall survival (OS) and progression-free survival (PFS), we identified TRIM59 as the primary research target. TRIM59 was markedly overexpressed in pRCC tissues, and correlated with poor OS. Functional studies showed that TRIM59 knockdown inhibited pRCC cell proliferation and induced mitochondrial-related apoptosis both in vitro and in vivo. Mechanistically, TRIM59 facilitated K27- and K63-linked ubiquitination and degradation of Acetyl-CoA Acetyltransferase 1 (ACAT1) at lysine 174 (K174), a critical enzyme in mitochondrial lipid metabolism. This disruption of lipid homeostasis in clear cell renal carcinoma (pRCC), particularly in mitochondrial cardiolipin metabolism, inhibited mitochondria-dependent apoptosis and, consequently, enhanced tumorigenesis. These findings suggest TRIM59 as a biomarker and potential therapeutic target, supporting precision oncology strategies for pRCC treatment.