ACACA modulates R-loop homeostasis to enhance lipid metabolism and microenvironmental interactions in ccRCC

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• R-loops are nucleic acid structures involved in genome regulation and instability.
• Their role in the clear cell renal cell carcinoma (ccRCC) tumor microenvironment (TME) is not well understood.

Purpose of the Study:

• To investigate R-loop activity in ccRCC and its association with clinical outcomes.
• To identify key R-loop-associated genes and their functional roles in ccRCC progression.

Main Methods:

• Integrated ccRCC transcriptomic and clinical data.
• Applied single-sample gene set enrichment analysis (ssGSEA) to quantify R-loop activity.
• Developed prognostic models using linear machine-learning algorithms.
• Utilized single-cell and spatial transcriptomics.
• Conducted in vitro and xenograft experiments.

Main Results:

• Elevated R-loop activity correlated with advanced ccRCC and poor prognosis.
• ACACA emerged as a dominant prognostic gene linked to metabolic reprogramming.
• ACACA expression was high in malignant cells, involved in lipid metabolism signaling.
• ACACA promoted ccRCC cell proliferation and migration while reducing apoptosis.
• ACACA modulated R-loop accumulation, fatty acid metabolism, and mitochondrial function.

Conclusions:

• ACACA acts as an R-loop-associated metabolic driver in ccRCC.
• It connects genomic stress to lipid reprogramming and TME remodeling.
• ACACA shows potential as a prognostic biomarker and therapeutic target for ccRCC.