Upregulation of SIRT1 ameliorates apoptosis of rat nucleus pulposus cells under oxidative stress through FoxO1/β-catenin pathway

Introduction: Age-related degenerative changes in intervertebral discs (IVDs) can lead to lower back pain, and even paralysis. This topic is therefore garnering growing attention in an increasingly ageing society. The oxidative stress-induced degenerative process is a major contributor to Apoptosis in nucleus pulposus cells. However, the regulatory mechanism of NAD-dependent protein deacetylase Sirtuin-1 (SIRT1) on Apoptosis in oxidative stress-induced rat nucleus pulposus cells remains unclear.

Material and methods: Rat nucleus pulposus cells (NPCs) were induced to undergo degenerative changes through H₂O₂ exposure, simulating the ageing oxidative stress process. Subsequently, the SIRT1 Activator SRT2104 was employed to explore the impact of SIRT1 on the expression of markers of ageing oxidative stress process in NPCs. The FOXO1 inhibitor AS1842856 was used to investigate the role of the downstream signalling pathway FOXO1/β-catenin in ageing NPCs under the influence of SRT2104. TUNEL staining and Other assays such as CCK were used to observe the effects of H₂O₂ on cell Apoptosis and viability, respectively. The influence of the aforementioned treatments on the ageing phenotype was observed through β-galactosidase staining, immunofluorescence staining, flow cytometry analysis, and protein electrophoresis.

Results: Under H₂O₂-induced oxidative stress, both the mRNA and protein levels of SIRT1 decreased in rat NPCs. Conversely, specific activation of SIRT1 inhibited Apoptosis and reduced the expression of senescence-associated secretory phenotype (SASP) and ageing-related proteins. Meanwhile, inhibiting FOXO1 expression with AS1842856 significantly upregulated β-catenin protein levels, suppressing the Apoptosis process in ageing NPCs under oxidative stress.

Conclusions: These results suggest that activation of the SIRT1/FOXO1/β-catenin axis can diminish ageing-related phenotypes and cell Apoptosis in NPCs, inhibiting the oxidative stress-induced ageing process triggered by H₂O₂. These findings may offer a new perspective for the treatment of intervertebral disc degeneration (IDD) in the future.

FoxO1; SIRT1; apoptosis; nuclear pulposus cells; senescence; β-catenin.