2. Academic Validation
  3. Eupalinolide B alleviates rheumatoid arthritis through the promotion of apoptosis and autophagy via regulating the AMPK/mTOR/ULK-1 signaling axis

Eupalinolide B alleviates rheumatoid arthritis through the promotion of apoptosis and autophagy via regulating the AMPK/mTOR/ULK-1 signaling axis

  • Int Immunopharmacol. 2025 Feb 20:148:114179. doi: 10.1016/j.intimp.2025.114179.
Sheng-Long Gu 1,  Xue-Song Liu 1,  Ze-Shan Xu 1,  Ling-Ling Li 1,  Xin-Jie Wu 2,  Fei-Long Li 1,  Yan Huang 1,  Xiang Ran 3,  Rong Li 4
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China.
  • 2 The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China.
  • 3 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China. Electronic address: ranxiang@ahmu.edu.cn.
  • 4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230026, Anhui Province, China. Electronic address: aydlirong@163.com.
PMID: 39874849 DOI: 10.1016/j.intimp.2025.114179
Abstract

The excessive proliferation of fibroblast-like synoviocytes (FLS) leads to synovial hyperplasia, a key pathological hallmark of rheumatoid arthritis (RA). Eupalinolide B (EB), a sesquiterpene lactone of Eupatorium lindleyanum DC., has anti-inflammatory effects and anti-proliferative activity in tumor cells. However, its potential use in RA treatment is unclear. This study explored EB's anti-rheumatoid activities by promoting Apoptosis and Autophagy in RA-FLS and the synovium of adjuvant-induced arthritis (AIA) rats, focusing on its regulation of the AMPK/mTOR/ULK-1 axis. Our findings revealed that EB inhibited proliferation, induced Apoptosis, and promoted Autophagy in RA-FLS. Autophagy inhibition using 3-methyladenine (3-MA) diminished EB's anti-proliferative effects, suggesting that EB promotes RA-FLS Autophagy as a death mechanism. Z-VAD-FMK, a pan-caspase inhibitor, decreased EB-induced Autophagy, while 3-MA co-treatment reduced Caspase-3 activity, demonstrating that EB-induced Apoptosis and Autophagy promoted each Other to support its anti-proliferative effects. In vivo, EB exhibited clear anti-arthritic effects in AIA rats, as shown by reduced paw swelling, arthritis index, serum levels of TNF-α, IL-1β, and MCP-1, and joint damage, along with decreased Ki67 expression, increased Apoptosis, and enhanced Autophagy in AIA rat synovium. Mechanistically, EB regulated the AMPK/mTOR/ULK-1 axis in RA-FLS and AIA rat synovium, as evidenced by higher expression of p-AMPK and p-ULK-1 and lower levels of p-mTOR. Notably, co-treatment of the AMPK Inhibitor compound C negated EB's beneficial effects in RA-FLS and AIA rats. Collectively, EB demonstrated exact anti-RA effects by inducing Apoptosis and Autophagy via the regulation of the AMPK/mTOR/ULK-1 axis, highlighting its potential for RA therapy.

Keywords

AMPK/mTOR/ULK-1 pathway; Apoptosis; Autophagy; Eupalinolide B; Fibroblast-like synoviocytes; Rheumatoid arthritis.

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