Site 1 protease aggravates acute kidney injury by promoting tubular epithelial cell ferroptosis through SIRT3‐SOD2‐mtROS signaling

Ischemia/reperfusion (I/R)‐induced acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality. Ferroptosis, a newly discovered form of oxidative cell death, is involved in the pathogenesis of renal I/R injury; however, the underlying mechanism remains to be explored. Here, we reported that site 1 protease (S1P) promotes ischemic kidney injury by regulating ferroptotic cell death of tubular epithelial cells. S1P abundance was measured in hypoxia/reoxygenation (H/R)‐treated Boston University mouse proximal tubular (BUMPT) cells and I/R‐induced murine kidney tissue. S1P expression in BUMPT cells and kidneys was initially activated by hypoxic stimulation, accompanied by the ferroptotic response. Blocking S1P blunted H/R‐induced ferroptotic cell death, which also restored sirtuin 3 (SIRT3) expression and superoxide dismutase 2 (SOD2) activity in BUMPT cells. Next, inhibition of S1P expression restored I/R‐suppressed SIRT3 abundance, SOD2 activity and reduced the elevated level of mitochondria reactive oxygen species (mtROS), which attenuated tubular cell ferroptosis and renal I/R injury. In conclusion, S1P promoted renal tubular epithelial cell ferroptosis under I/R status by activating SIRT3‐SOD2‐mtROS signaling, thereby accelerating kidney injury. Thus, targeting S1P signaling may serve as a promising strategy for I/R kidney injury. In this study, the authors show that expression of site 1 protease (S1P) was induced by hypoxia in vitro and in vivo, resulting in decreased SIRT3 expression and subsequent suppression of deacetylation and activity of SOD2, leading to the enhanced generation of mitochondrial reactive oxygen species (ROS), which promoted tubular epithelial cell ferroptosis to accelerate ischemia/reperfusion‐induced acute kidney injury.