NOV promotes renal ischemia-reperfusion injury by driving TFRC-dependent ferroptosis.

Abstract

Acute kidney injury (AKI) is a severe clinical syndrome with limited therapeutic options, and its underlying molecular mechanisms remain incompletely understood. Nephroblastoma overexpressed (NOV), a matricellular protein, has been implicated in renal pathophysiology; however, its role in AKI remains unclear. Using a murine renal ischemia-reperfusion (I/R) model and HK-2 cells subjected to hypoxia/reoxygenation (H/R), we found that NOV was rapidly induced in renal tubular epithelial cells (RTECs) during the early phase of AKI. RTEC-specific NOV knockdown significantly alleviated renal dysfunction and tubular injury after I/R. Transcriptomic analysis implicated ferroptosis as a major pathway regulated by NOV. Consistently, NOV knockdown attenuated lipid peroxidation, iron accumulation, and ferroptosis-associated injury both in vivo and in vitro. NOV overexpression increased ferroptotic susceptibility under H/R, and ferrostatin-1 attenuated these effects. Mechanistically, NOV interacted with transferrin receptor (TFRC) and promoted ferroptosis by stabilizing TFRC through reduced K48-linked ubiquitination. NEDD4L was identified as a candidate E3 ligase mediating TFRC ubiquitination, and NOV disrupted NEDD4L-associated K48-linked ubiquitination of TFRC. Collectively, these findings identify the NOV-TFRC axis as a regulator of ferroptotic tubular injury and suggest NOV as a potential therapeutic target in I/R-AKI.