<p>Renal tubular epithelial cells (TECs), which are highly susceptible to injury during acute kidney injury (AKI), have notable regenerative effects on renal recovery after AKI. AKI-driven metabolic reprogramming of TECs plays a critical role in determining whether kidneys recover functionally or develop fibrosis. Targeting the metabolism of TECs offers valuable insights into AKI treatment. Growth hormone-releasing hormone (GHRH) and its analog GHRH peptide (GHRP) play beneficial roles in the field of regenerative medicine. Here, we designed a self-assembling GHRP-6 peptide hydrogel, and we hypothesized that this hydrogel could reprogram the metabolism of TECs, further enhancing recovery from AKI. Metabolomic sequencing analysis revealed that spermidine, L-glutamine, and acetyl-CoA, which are involved in amino acid and fatty acid metabolism, were highly enriched in a mouse model of AKI treated with the GHRP-6 hydrogel. Further study revealed that GHRP-6 hydrogel treatment enhanced the survival of TECs in the ischemic microenvironment by activating the mTOR-P70 pathway. In conclusion, GHRP-6 hydrogel treatment has beneficial therapeutic effects on AKI through the targeting of metabolic reprogramming, which offers a novel therapeutic strategy to protect TECs in AKI treatment.</p> Graphic abstract <p></p>