Shuting Tong, Xin Li, Fangying Wang, Qi Cheng, Peiyu Zhang, Mo Chen, Yifan Xie, Xiaoyong Lu, Huaxiang Wu

Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China

Correspondence: Huaxiang Wu, Email wuhx8855@zju.edu.cn Xiaoyong Lu, Email luxyzju18@zju.edu.cn

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. 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 Ficoll-Paque Plus density gradient centrifugation. A mouse model of gouty arthritis was established by injecting MSU crystal suspension into the foot pad. In vitro, PMA-differentiated THP-1 cells were stimulated with MSU crystals. We then investigated the effect of the ALDH2 agonist Alda-1 on MSU crystal-induced acute inflammation. Furthermore, the Nrf2 inhibitor ML385 was used to define the Nrf2 pathway’s role in mediating ALDH2 activation effects during acute gout attacks.
Results: We found that compared to healthy controls, ALDH2 expression was significantly decreased in the PBMCs 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.

Keywords: ALDH2, Nrf2, acute gouty arthritis, pyroptosis, reactive oxygen species (ROS)