Acute-on-chronic liver failure (ACLF) is a highly critical condition with an extremely high short-term mortality rate. Constrained by the shortage of donor livers for transplantation, clinical practice faces the severe challenge of a profound lack of effective “non-transplant therapies.” Deeply dissecting the molecular regulatory networks that drive liver regeneration and identifying novel molecular targets capable of effectively reversing liver injury are key to resolving the current clinical dilemmas in ACLF treatment.
The researchers innovatively focused on a novel class of non-coding RNAs—tRNA-derived small RNAs (tsRNAs). Utilizing small RNA sequencing technology, the study found that the expression level of tsRNA-Gly is significantly downregulated in ACLF liver tissues. Functional assays indicated that the overexpression of tsRNA-Gly can significantly promote hepatocyte regeneration. Mechanistically, tsRNA-Gly directly binds to acylpeptide hydrolase (ACPH) through a specific recognition sequence. This interaction inhibits the ubiquitin-proteasome-mediated degradation of ACPH, thereby activating grainyhead-like 1 (GRHL1) and promoting its nuclear translocation. This process ultimately upregulates the transcription of Cyclin D1 (CCND1), driving hepatocyte regeneration (Figure 1).
The revelation of the tsRNA-Gly/ACPH/GRHL1 signaling axis not only proves that tsRNAs possess profound biological functions within the molecular regulatory network of liver regeneration, but also provides a highly promising novel molecular target for clinical intervention in ACLF. This discovery is expected to drive the development of new, non-transplant targeted drugs in the future.
Mingxue Yu, Wenli Xu, Guanzi Chen and Yucheng Lei are the co-first authors of this study， Qiyi Zhao, Yusheng Jie, and Yutian Chong (all from The Third Affiliated Hospital of Sun Yat-sen University) are the co-corresponding authors.
Science China Life Sciences