Recent Insights Into Wnt‐Related tRNA‐Derived Fragments (tRFs) in Human Diseases

ABSTRACT tRNA‐derived fragments (tRFs) are a newly recognized class of small noncoding RNAs (sncRNAs) that play significant roles in various diseases. The Wnt pathway plays a key role in various physiological processes such as embryonic development, tissue renewal and regeneration. In the regulation of Wnt/β‐catenin, Forkhead box k1( FOXK1 ), Frizzled class receptor 3 ( FZD3 ), and Wnt5b can be targeted and inhibited by three tRFs: tRF3008A targets FOXK1 to inhibit colorectal cancer (CRC), 5′‐tiRNAVal targets FZD3 to inhibit breast cancer (BrC), and tRF‐22‐8BWS7K092 targets Wnt5b to induce ferroptosis in lung cells. Additionally, tRF‐24‐V29K9UV3IU can inhibit the levels of FZD3, Van Gogh‐like protein 1 (VANGL1), and cyclin D2 (CCND2) through an unexplained mechanism and play a role in inhibiting gastric cancer (GC). Clinical data has shown that the expression levels of certain tRFs are associated with the prognosis and pathological features of CRC and BrC patients. Low expression of tRF3008A is associated with poor prognosis and adverse pathological features in CRC patients, while high expression of tiRNA‐Phe‐GAA‐003 and low expression of 5′‐tiRNAVal are associated with poor prognosis and adverse pathological features in BrC patients. KEGG analysis has also shown that a variety of tRFs are involved in regulating the Wnt pathway and have been shown to play a role in a variety of diseases. For example, high expression of tRF‐Gly‐CCC‐039 is associated with poor healing of diabetic foot, low expression of tsRNA‐10277 is associated with high incidence of steroid‐induced osteonecrosis of the femoral head (SONFH), high expression of tRF‐22‐8BWS7K092 is correlated with the severity of acute lung injury (ALI), and low expression of tsRNA‐21109 is associated with the severity of systemic lupus erythematosus (SLE), and high expression of tRF‐36‐F900BY4D‐84KRIME and tRF‐23‐87R8WP9IY, as well as low expression of tRF‐40‐86J8WPMN1E8Y7Z2R, were associated with high incidence of varicose vein (VV), and high expression of ts‐34, was associated with high mortality of BrC. This article summarizes the biological function and mechanism of tRFs related to the Wnt pathway in cancer and other diseases, providing a new direction for subsequent translational medical research.