A molecular switch that helps blood vessels grow may connect two seemingly separate processes in cancer and tissue biology: the loss of insulin-like growth factor binding protein 5 (IGFBP5) and a chemical modification of the messenger RNA encoding fibroblast growth factor 16 (FGF16). In a study published in Experimental & Molecular Medicine, Song, Hu, Hong and colleagues report that METTL14-dependent N6-methyladenosine, or m6A, modification of FGF16 participates in the enhanced angiogenesis associated with IGFBP5 deficiency. The findings place RNA modification at the center of a signaling pathway that could influence how tissues build new vascular networks.
Angiogenesis is the formation of new blood vessels from existing ones. It is essential during development, wound repair and the restoration of blood flow after injury, but it can also support disease. Tumors, for example, can stimulate nearby vessels to grow toward them, supplying oxygen and nutrients that enable continued expansion. Because angiogenesis depends on precisely coordinated signals between cells, changes in growth factors, RNA stability and gene expression can have substantial effects on vascular behavior.
IGFBP5 belongs to a family of proteins that bind insulin-like growth factors and regulate their availability and activity. Although its biological effects vary according to cell type and context, IGFBP5 has been implicated in tissue remodeling, cell survival and vascular regulation. The new study focuses on what happens when IGFBP5 is deficient, describing a state in which angiogenesis is enhanced. The researchers identify FGF16 as part of the molecular response, suggesting that the effects of IGFBP5 loss extend beyond conventional protein signaling and into the post-transcriptional control of gene expression.
FGF16 is a member of the fibroblast growth factor family, a group of secreted or membrane-associated signaling proteins involved in proliferation, differentiation and tissue repair. Fibroblast growth factors typically act by binding fibroblast growth factor receptors on the cell surface, activating intracellular pathways that can alter cell migration, survival and growth. In the context of blood-vessel formation, such signals may affect endothelial cells—the specialized cells that line blood vessels—encouraging them to move, multiply and organize into vessel-like structures.
The study highlights m6A, the most common internal chemical modification found in messenger RNA in many mammalian cells. Messenger RNA carries genetic instructions from DNA to ribosomes, where proteins are produced. Adding or removing m6A can change how long an RNA molecule survives, how efficiently it is translated, where it travels within a cell or whether it is selectively degraded. In this regulatory system, METTL14 functions as an essential component of the methyltransferase machinery that deposits m6A marks, working with other proteins to identify and modify specific RNA transcripts.
According to the researchers, METTL14-dependent m6A modification affects FGF16 in the setting of IGFBP5 deficiency. This provides a mechanistic link between reduced IGFBP5, altered RNA chemistry and increased blood-vessel formation. Rather than changing the DNA sequence of FGF16, the pathway appears to regulate the transcript after it has been produced. Such a mechanism could allow cells to rapidly adjust the amount or activity of FGF16 in response to changes in their environment, including signals associated with tissue stress or remodeling.
The significance of the finding lies in the way it integrates several layers of cellular regulation. IGFBP5 deficiency represents an upstream change in the tissue environment. METTL14 supplies an RNA-modifying activity, while FGF16 provides a downstream growth signal capable of influencing vascular cells. Together, these components form a possible regulatory axis in which the availability of one protein reshapes the fate and function of another gene’s messenger RNA. This kind of layered control is increasingly recognized as a defining feature of angiogenic biology.
The work may be especially relevant to diseases in which abnormal vessel growth is beneficial or harmful. Blocking an excessive vascular response could be useful in conditions such as cancer or certain eye diseases, whereas stimulating angiogenesis may help repair poorly perfused tissues. However, the study does not by itself establish that METTL14, m6A-modified FGF16 or IGFBP5 can be safely targeted in patients. These molecules participate in multiple biological processes, and altering them could produce effects in organs or cell types beyond the blood-vessel system.
Future research will need to clarify exactly how the m6A mark changes FGF16 RNA behavior. Key questions include whether modification increases transcript stability, enhances protein production, changes RNA localization or affects interactions with m6A reader proteins that interpret the chemical signal. Researchers will also need to determine which cells are responsible for the relevant changes, whether the pathway operates in human disease samples and how it interacts with established angiogenic regulators such as vascular endothelial growth factor.
By identifying an RNA-modification pathway associated with IGFBP5 deficiency-enhanced angiogenesis, the study adds a new layer to the molecular map of blood-vessel growth. Its central message is that angiogenic signals are not controlled only at the level of secreted proteins and cell-surface receptors. They can also be tuned through chemical marks placed on messenger RNA. If validated in further experimental models, the METTL14–m6A–FGF16 axis could become a useful framework for understanding how tissues reprogram vascular growth—and for designing future therapies that adjust that response with greater precision.
Subject of Research: METTL14-dependent m6A modification of FGF16 in IGFBP5 deficiency-enhanced angiogenesis.
Article Title: METTL14-dependent N6-methyladenosine modification of FGF16 participates in IGFBP5 deficiency-enhanced angiogenesis.
Article References: Song, F., Hu, Y., Hong, YX. et al. “METTL14-dependent N6-methyladenosine modification of FGF16 participates in IGFBP5 deficiency-enhanced angiogenesis.” Experimental & Molecular Medicine (2026). https://doi.org/10.1038/s12276-026-01788-y
Image Credits: AI Generated
DOI: 10.1038/s12276-026-01788-y
Keywords: METTL14, m6A RNA modification, FGF16, IGFBP5, angiogenesis, blood-vessel growth, endothelial cells, epitranscriptomics, fibroblast growth factors.
