tsRNA modifications: An emerging layer of biological regulation in disease

[Display omitted] •tsRNAs manifest uniquely in various tumor or pathological scenarios, functioning via diverse mechanisms.•The modification patterns and sites of tRNA play a crucial role in affecting the production efficiency of tsRNAs and determining their specific locations among tsRNAs.•Endogenous tsRNAs in organisms are derived from tRNAs with many modifications, such as m7G and m5C-modified tsRNAs, m1A-modified tRF-3b, and Ψ-modified tsRNAs, play important roles in biological regulation.•Modified tsRNA not only demonstrate enhanced stability but also exhibit distinct modification-dependent regulatory effects compared to unmodified tsRNAs.•A novel m7G-3′tiRNA regulates protein post-translational mechanism that promotes cancer progression. Transfer RNA (tRNA)-derived small RNA (tsRNA) represents an important and increasingly valued type of small non-coding RNA (sncRNA). The investigation of tRNA and tsRNA modification crosswalks has not only provided novel insights into the information and functions of tsRNA, but has also expanded the diversity and complexity of the tsRNA biological regulation network. Comparing with other sncRNAs, tsRNA biogenesis show obvious correlation with RNA modifications from mature tRNA and harbor various tRNA modifications. In this review, we aim to present the current aspect of tsRNA modifications and that modified tsRNA shape different regulatory mechanisms in physiological and pathological processes. Strategies for studying tsRNA mechanisms include its specific generation and functional effects induced by sequence/RNA modification/secondary structure. tsRNAs could harbor more than one tRNA modifications such as 5-methylcytosine (m5C), N1-methyladenosine (m1A), pseudouridine (Ψ) and N7-methylguanosine (m7G). This review consolidates the current knowledge of tRNA modification regulating tsRNA biogenesis, outlines the functional roles of various modified tsRNA and highlights their specific contributions in various disease pathogenesis. Therefore, the improvement of tsRNA modification detection technology and the introduction of experimental methods of tsRNA modification are conducive to further broadening the understanding of tsRNA function at the level of RNA modification.