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

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.