RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Abstract

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

Fig. 1

The milestone events in RNA modification field. The first RNA modification type Pseudouridine (Ψ) was discovered in 1951. Since then, other RNA modification, including m6A, m1A, m6Am, etc were discovered. Along with the accumulation of epi-transcriptomic knowledge, comprehensive databases like RNAMDB and MODOMICS were incepted. Since Liquid Chromatograph-Mass Spectrometer (LC-MS) technique was utilized for the quantitative analysis of modified ribonucleosides in 2015, more specific high-throughput mapping methods gradually emerged. Recent years have witnessed the application of single-cell sequencing technologies in mapping RNA modification. The figure is generated with BioRender (https://biorender.com)

Fig. 2

The chemical structure, distribution, and molecular functions of eight RNA modifications. Chemical modification occurs on many types of RNA and modulate every links of RNA metabolism. m6A N6-methyladenosine, m6Am N6,2′-O-dimethyladenosine, m5C 5-methylcytosine, m1A N1-methyladenosine, m7G 7-methylguanosine, ac4C N4-acetylcytidine, ψ pseudouridine, A-to-I editing adenosine-to-inosine RNA editing, CDS coding sequence, UTR untranslated regions, pri-miRNA primary microRNA, pre-miRNA precursor microRNA. The figure is generated with BioRender (https://biorender.com)

Fig. 3

The roles of RNA modifications in glucose metabolism. The schematic diagram shows the direct regulation of RNA modification on glucose metabolism pathways. The key glycolytic enzymes, such as hexokinase (HK), enolase (ENO), Aldolase A (ALDOA), pyruvate kinase isozyme M1/2 (PKM1/2), pyruvate dehydrogenase kinase (PDK), lactate dehydrogenase (LDH) and glucose transporter (GLUT) are crucial targets of dysregulated RNA modifiers, and are generally upregulated in various pathologies. The figure is generated with BioRender (https://biorender.com)

Fig. 4

The roles of RNA modifications in lipid and amino acid metabolism. For lipid metabolism, key enzymes in FA synthesis, including fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase1 (SCD1), and ACLY, are significant targets of RNA modifications. Relevant studies on amino acid metabolism are limited. The figure is generated with BioRender (https://biorender.com)

Fig. 5

Epigenetic regulation of RNA modification on metabolism in diseases. RNA modifications broadly regulated metabolic pathways in diverse diseases, covering glucose (green box), lipid (blue box), amino acid and mitochondrial (yellow box) metabolism. As intuitively shown in the picture, Gastric cancer (GC), Colorectal Cancer (CRC), Hepatocellular Carcinoma (HCC), Acute Myeloid Leukemia (AML), and Breast Cancer (BRCA) are especially related to RNA modifications-mediated metabolic deregulations. The figure is generated with BioRender (https://biorender.com)

Fig. 6

Effects of RNA modification on immunometabolism. This figure shows current findings about how RNA modifications regulate immunometabolism. On the one hand, RNA modifications are involved in the intrinsic metabolic adaptation of immune cells, further affecting function and state of immunocytes. On the other hand, m6A modification could mediate several phenotype alterations of immunocytes induced by glucose deficiency and high lactate in TME. The figure is generated with BioRender (https://biorender.com)