DPP8 and DPP9 promote tubular epithelial cell ferroptosis in acute kidney injury.

Abstract

Renal tubular epithelial cells (TECs) death plays vital role in acute kidney injury (AKI). However, the effects and regulated mechanisms of ferroptosis within TECs during AKI has not been fully elucidated. Here, we found evidence that ferroptosis pathway was significant enriched in injured TECs and associated with excessive expression of Dpp8 and Dpp9, observed in snRNA-seq of AKI mice. Consistently, elevated protein levels of DPP8 and DPP9 were observed in TECs from both AKI patients and murine models, concomitant with ferroptotic cell death. TC-E5007, a combined inhibitor of DPP8 and DPP9, could significantly protect TECs from ferroptosis in vivo, thereby improving the renal function, alleviating tubulointerstitial injury and reducing renal inflammation in cisplatin-related AKI mice. Furthermore, in vitro siRNA-mediated knockdown of DPP8 and DPP9 decreased ferroptosis in cisplatin-treated HK-2 cells, respectively. Collectively, our findings reveal DPP8 and DPP9 as regulators of ferroptosis in TECs and propose them as promising therapeutic targets for mitigating AKI progression.