Glutamine mitigates oxidative stress-induced matrix degradation, ferroptosis, and pyroptosis in nucleus pulposus cells via deubiquitinating and stabilizing Nrf2.

AIMS: Intervertebral disc degeneration (IDD) is closely related to low back pain (LBP), which is a prevalent age-related problem worldwide; however, the mechanism underlying IDD is unknown. Glutamine, a free amino acid prevalent in plasma, is recognized for its anti-inflammatory and antioxidant properties in various diseases, the current study aims to clarify the effect and mechanism of glutamine in IDD.

RESULTS: A synergistic interplay was observed between pyroptosis and ferroptosis within degenerated human disc specimens. Glutamine exhibited significant efficacy in mitigating IDD in both ex-vivo and in-vivo experimental models. Moreover, glutamine protected nucleus pulposus (NP) cells after tert-butyl hydroperoxide (TBHP)-induced pyroptosis, ferroptosis, and extracellular matrix (ECM) degradation in vitro. Glutamine protected NP cells from TBHP-induced ferroptosis by promoting Nrf2 accumulation by inhibiting its ubiquitin-proteasome degradation and inhibiting lipid oxidation.

INNOVATION AND CONCLUSIONS: A direct correlation is evident in the progression of IDD between the processes of pyroptosis and ferroptosis. Glutamine suppressed oxidative stress-induced cellular processes, including pyroptosis, ferroptosis, and ECM degradation through deubiquitinating Nrf2 and inhibiting lipid oxidation in NP cells. Glutamine is a promising novel therapeutic target for the management of IDD.