2. Academic Validation
  3. Salvianolic acid B alleviates rheumatoid arthritis by inhibiting oxidative stress and pyroptosis through the Keap1-Nrf2/ROS/NLRP3 axis

Salvianolic acid B alleviates rheumatoid arthritis by inhibiting oxidative stress and pyroptosis through the Keap1-Nrf2/ROS/NLRP3 axis

  • Phytomedicine. 2025 Dec 23:150:157736. doi: 10.1016/j.phymed.2025.157736.
Meng-Yuan Zhou 1,  Zi-Yao Gao 1,  Wen-Cai Long 1,  Juan Zhou 1,  Meng Zhang 1,  Xue-Na Gong 2,  Yan-Xin Zhou 2,  Li Cai 3,  Rong Li 4
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
  • 2 Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui Province 230032, China.
  • 3 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province 230022, China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui Province 230032, China. Electronic address: [email protected].
  • 4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui Province 230026, China. Electronic address: [email protected].
PMID: 41456526 DOI: 10.1016/j.phymed.2025.157736
Abstract

Background: Rheumatoid arthritis (RA) is marked by chronic synovial inflammation and systemic immune dysregulation, in which oxidative stress and Pyroptosis play critical pathogenic roles. Salvianolic acid B (SalB), a major polyphenolic compound derived from Salvia miltiorrhiza, exhibits potent antioxidant and anti-inflammatory activities that confer therapeutic benefits in RA.

Purpose: To clarify SalB's therapeutic potential and underlying mechanisms in RA.

Methods: The anti-RA effects of SalB were assessed in adjuvant-induced arthritis (AIA) rats and RA fibroblast-like synoviocytes (RA-FLS). Bioinformatics analysis was performed to identify the crucial regulatory pathways. The involvement of the Keap1-Nrf2 pathway and its downstream ROS-NLRP3-pyroptosis axis was examined using in vitro and in vivo approaches.

Results: SalB alleviated synovial inflammation, pannus formation, and joint damage in AIA rats. In RA-FLS, it suppressed tumor necrosis factor-α-induced proliferation, migration, invasion, and cytoskeletal remodeling. SalB enhanced Nrf2 nuclear translocation and upregulated the antioxidant Enzymes NQO1 and HO-1, thereby reducing ROS accumulation and preventing ROS-dependent activation of the NLRP3 inflammasome. Consequently, cleavage of Caspase-1 and GSDMD and the release of IL-18 and IL-1β were diminished, alleviating Pyroptosis and inflammation. Notably, pharmacological inhibition of Nrf2 by ML385 significantly attenuated the effects of SalB in vitro. Mechanistically, various experimental approaches, including cellular thermal shift assays, molecular docking, and mutational analyses, confirmed that SalB directly binds to Keap1 at Arg415 and disrupts its inhibitory interaction with Nrf2.

Conclusions: SalB alleviates RA by mitigating oxidative stress and Pyroptosis through Keap1-Nrf2/ROS/NLRP3 signaling. This study provides a solid mechanistic basis for SalB's future therapeutic research in RA.

Keywords

Keap1-Nrf2; NLRP3 inflammasome; Oxidative stress; Pyroptosis; Rheumatoid arthritis; Salvianolic acid B.

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