Background: Gouty arthritis is a common disease characterized by the deposition of monosodium urate (MSU) crystals in joint and non-joint structures. Nonetheless, the role of aldehyde dehydrogenase 2 (ALDH2) in the pathophysiology of acute gout remains unclear.

Objectives: This study aimed to evaluate the role of ALDH2 in MSU crystal-induced acute gout attacks and related mechanisms and to identify potential therapeutic strategies for gout management.

Methods: Peripheral blood mononuclear cells (PBMCs) from gout patients and healthy controls were isolated via centrifugation using Ficoll-Paque Plus solution. The mouse model of gouty arthritis was established through the injection of MSU crystal suspension into the foot pad, while the in vitro model was created by stimulating PMA-induced THP-1 cells with MSU crystals for 12 hours. Subsequently, we assessed the effect of the ALDH2 agonist Alda-1 on MSU crystal-induced acute inflammation. We measured the extent of swelling in the foot pads of mice and employed various methods to evaluate inflammation, cellular damage, and oxidative stress. Additionally, the Nrf2 inhibitor ML385 was utilized to further elucidate the role of the Nrf2 pathway in the effects of ALDH2 on acute gout attacks.

Results: We found that compared to healthy controls, ALDH2 expression was significantly decreased in the peripheral blood mononuclear cells of patients with acute gout and negatively correlated with C-reactive protein levels. In mice models with acute gout, treatment with Alda-1 effectively mitigated MSU-induced footpad edema, along with reductions in inflammatory cell infiltration and pro-inflammatory cytokine production in the local tissue of the footpad. In vitro studies demonstrated that Alda-1 significantly reduced oxidative stress induced by MSU crystal stimulation and suppressed the activation and assembly of the NLRP3 inflammasome, as well as the resulting pyroptosis. Further experiments revealed that Alda-1 treatment promoted Nrf2 nuclear translocation, alleviating oxidative stress and cellular inflammation.

Conclusion: Our findings suggest that Alda-1-mediated activation of ALDH2 can alleviate MSU-induced oxidative stress and inflammation by regulating the Nrf2/ROS pathway and may represent a promising therapeutic strategy for managing acute gouty arthritis.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.