Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=41354870&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Lysophosphatidylethanolamine 18:1 drives clear cell renal cell carcinoma by stabilizing SIRT6 to reprogram lipid metabolism #MMPMID41354870
Yue N; Zhao H; Zhang Y; Gu J; Qi J; Wen J; Wang W; Lv M; Sun H; Chen J; Yang C; Qu C; Chen X; Yang Z
Signal Transduct Target Ther 2025[Dec]; 10 (1): 398 PMID41354870show ga
Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.
Signal+Transduct+Target+Ther 2025 ; 10 (1): 398
