Fibrillarin is a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation across evolution from Archaea to humans. It has been reported that fibrillarin is involved in the methylation of histone H2A in nucleoli and other processes, including viral progression, cellular stress, nuclear shape, and cell cycle progression. We show that fibrillarin has an additional activity as a ribonuclease. The activity is affected by phosphoinositides and phosphatidic acid and insensitive to ribonuclease inhibitors. Furthermore, the presence of phosphatidic acid releases the fibrillarin-U3 snoRNA complex. We show that the ribonuclease activity localizes to the GAR (glycine/arginine-rich) domain conserved in a small group of RNA interacting proteins. The introduction of the GAR domain occurred in evolution in the transition from archaea to eukaryotic cells. The interaction of this domain with phospholipids may allow a phase separation of this protein in nucleoli.

Long non-coding RNAs (lncRNAs) interact with a variety of biomolecules, including DNA, mRNAs, microRNA, and proteins, to regulate various cellular processes. Recently, their interactions with lipids have gained increasing attention as an emerging research area. Both lipids and lncRNAs play central roles in cellular regulation, and growing evidence reveals a complex interplay between these molecules. These interactions contribute to key biological functions, such as cancer progression, lipid droplet transport, autophagy, liquid−liquid phase separation, and the formation of organelles without membranes. Understanding the lipid−lncRNA interface opens new avenues for unraveling cellular regulation and disease mechanisms, holding great potential not only for elucidating the fundamental aspects of cellular biology but also for identifying innovative therapeutic targets for metabolic disorders and cancer. This review highlights the biological relevance of lipid–lncRNA interactions by exploring their roles in cellular organization, regulation, and diseases, including metabolic and cancer-related disorders.