Related Experiment Video
Updated: Aug 16, 2026
Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
NOV promotes renal ischemia-reperfusion injury by driving TFRC-dependent ferroptosis
Yanlu Xin1, Xiao Sun2, Ningxin Zhang1
1Department of Nephrology, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266003, China.
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.
Insights
Nephroblastoma overexpressed (NOV) protein drives ferroptosis in acute kidney injury (AKI) by stabilizing the transferrin receptor (TFRC). Inhibiting NOV may offer a novel therapeutic strategy for ischemia-reperfusion AKI.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Pathology
Background:
- Acute kidney injury (AKI) presents significant therapeutic challenges due to poorly understood molecular mechanisms.
- Nephroblastoma overexpressed (NOV), a matricellular protein, has an unclear role in the pathophysiology of AKI.
Purpose of the Study:
- To investigate the role of NOV in renal ischemia-reperfusion (I/R) injury.
- To elucidate the molecular mechanisms by which NOV influences AKI, particularly ferroptosis.
Main Methods:
- Utilized a murine renal ischemia-reperfusion (I/R) model and HK-2 cells under hypoxia/reoxygenation (H/R).
- Performed RTEC-specific NOV knockdown, transcriptomic analysis, and assessed ferroptosis markers (lipid peroxidation, iron accumulation).
- Investigated the interaction between NOV and transferrin receptor (TFRC), including ubiquitination and the role of NEDD4L.
Main Results:
- NOV expression was rapidly induced in renal tubular epithelial cells (RTECs) during early AKI.
- NOV knockdown significantly reduced renal dysfunction and tubular injury in I/R models.
- NOV was found to promote ferroptosis by stabilizing TFRC via reduced K48-linked ubiquitination, disrupting the NEDD4L E3 ligase interaction.
Conclusions:
- The NOV-TFRC axis is a key regulator of ferroptotic tubular injury in I/R-AKI.
- NOV promotes ferroptosis by modulating TFRC stability through ubiquitination.
- NOV represents a potential therapeutic target for treating ischemia-reperfusion-induced AKI.
