# TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation

## TL;DR

TRIM21 promotes cell death in disc degeneration by breaking down a protein that protects against oxidative stress.

## Contribution

TRIM21's role in accelerating ferroptosis via SLC7A11 ubiquitination in IVDD is newly identified.

## Key findings

- TRIM21 is upregulated in degenerated discs and promotes ferroptosis in NPCs.
- TRIM21 binds and degrades SLC7A11, a key antioxidant protein, via ubiquitination.
- Inhibiting TRIM21 reduces ferroptosis and protects NPCs from oxidative damage.

## Abstract

Intervertebral disc degeneration (IVDD) is a common cause of chronic low back pain, and ferroptosis – an iron-dependent form of cell death – has been linked to oxidative stress-induced damage in nucleus pulposus cells (NPCs). This study focuses on the role of TRIM21, an E3 ubiquitin ligase, in regulating ferroptosis during IVDD. TRIM21 expression was analyzed in clinical IVDD samples and tert-butyl hydroperoxide (TBHP)-treated NPCs. Ferroptosis was measured by assessing cell viability, Fe2+/ROS accumulation, and lipid peroxidation. The mechanism was investigated through Co-immunoprecipitation (Co-IP), ubiquitination assays, and cycloheximide (CHX) chase experiments. Results revealed that TRIM21 was significantly upregulated in degenerated discs. Silencing TRIM21 alleviated TBHP-induced ferroptosis, reducing iron overload, ROS, and lipid peroxidation, while restoring antioxidant activity and modulating ferroptosis-related proteins. Ferrostatin-1 rescued TRIM21-overexpression-induced ferroptotic injury. Mechanistically, TRIM21 bound SLC7A11 and promoted its K48-linked ubiquitination and proteasomal degradation. SLC7A11 knockdown reversed the protective effect of TRIM21 silencing. Thus, TRIM21 exacerbates IVDD by driving ferroptosis through ubiquitin-mediated degradation of SLC7A11, highlighting its potential as a therapeutic target.