LD-associated signatures identified by perilipin-based proximity labeling proteomics reveal GNA14 as a therapeutic and prognostic target in renal cell carcinoma.

Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), is characterized by metabolic reprogramming, notably disordered lipid metabolism and prominent intracellular lipid droplet accumulation. In addition to abnormal triglyceride and cholesterol ester storage, lipid droplets promote tumor proliferation, survival, and drug resistance by supplying energy, membrane components, and signaling platforms, thereby representing potential therapeutic targets. We integrated TMU-RNAseq and TCGA-KIRC datasets and performed proximity-labeling mass spectrometry targeting PLIN2/3 to identify perilipin-related genes (PRGs). Based on TCGA-KIRC, we established a lipid droplet-related model (LDM), and the LDM score (LDMS) effectively predicted ccRCC prognosis. Validation in TCGA-KIRC and three external cohorts (GSE22541, E-MTAB-1980, and E-MTAB-3267) showed superior prognostic performance over conventional clinical parameters. High LDMS was associated with increased mutation frequency and an immunosuppressive microenvironment. Drug sensitivity analysis suggested differential responses to Sorafenib, Cediranib, and Saracatinib. Functional assays demonstrated that GNA14 inhibits ccRCC progression and enhances lipid accumulation via PLIN2 upregulation. GNA14 overexpression combined with Lovastatin further strengthened antitumor effects. Overall, LDM is a robust prognostic tool, and GNA14 plus Lovastatin may offer a potential therapeutic strategy for ccRCC. On one hand, at a general level, overexpression of GNA14 in RCC significantly inhibits the proliferation, migration, and invasion of renal cancer cells, thereby exerting a suppressive effect on RCC. On the other hand, GNA14 interacts with PLIN2, leading to an increase in PLIN2 expression, which subsequently results in an enlargement of lipid droplet quantity and volume. This causes a notable rise in cholesterol and triglyceride levels within RCC cells, further facilitating RCC progression. Excitingly, lovastatin can partially block the detrimental pathway by which GNA14 promotes lipid accumulation. Therefore, combining lovastatin with GNA14 overexpression yields a more effective suppression of RCC.