The telomerase reverse transcriptase-derived peptide GN11 alleviates glycolysis and cellular senescence in the fibrotic kidney by inhibiting the TGF-β1/Smad3/lncRNA Oip5-os1/miR-30c-5p/Rock2 axis

Renal fibrosis represents the ultimate pathological manifestation of chronic kidney disease (CKD). To date, no clinically approved drugs that specifically target renal fibrosis are available. In this study, we discovered that GV1001(GV), a peptide fragment derived from human telomerase reverse transcriptase (hTERT), can inhibit the unilateral ureteral obstruction (UUO)-induced renal fibrosis. Through systematic fragment optimization, we identified GN11, an analog of GV with superior activity. The phenotypic analysis revealed that both GV and its optimized analog GN11 effectively attenuated glycolysis, cellular senescence and apoptotic phenotypes associated with renal fibrosis. Mechanistic investigations indicated that GN11 suppresses TGF-β1/Smad3 signaling while upregulates the expression of miR-30c-5p, leading to the downregulation of its target gene Rock2. Furthermore, GN11 reduces the expression of the lncRNA Oip5-os1, thereby diminishing its antagonistic effect on miR-30c-5p, which in turn amplifies the inhibitory effect on Rock2 expression. These findings suggest that GN11 has promising potential as a candidate molecule for the treatment of renal fibrosis and other types of organ fibrosis. Moreover, our research provides valuable insights and a scientific foundation for the development of novel therapeutic agents against renal fibrosis.