Authors
Yanlu Xin, Xiao Sun, Ningxin Zhang, Chen Guan, Liting Wang, Wei Ding, Minghao Gu, Zhuo Song, Ruizhe Zhao, Xinning Wang, Yan Xu
Published in
Cellular signalling. Pages 112826. Aug 14, 2026. Epub Aug 14, 2026.
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.
PMID:
42600717
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.
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