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<p>Rheumatoid arthritis (RA) is frequently complicated by chronic pain, anxiety and depression, yet the neuroimmune mechanisms linking peripheral inflammation to central affective dysfunction remain elusive. Here we demonstrate that the natural flavonoid dihydroquercetin (DHQ) blocks Trim14 and relieves pain-depression comorbidity in RA. Serum Trim14 is elevated in RA patients and correlates with clinical symptom severity. We identify Trim14 as a contributing factor of JAK1/STAT3 signaling in spinal dorsal horn neurons, promoting both nociceptive sensitization and affective symptoms in collagen-induced arthritis (CIA) mice. Intrathecal Trim14 siRNA attenuates synovial inflammation, inflammatory pain and anxiety-depressive behaviors. Molecular docking and molecular dynamics simulations reveal that DHQ occupies the Trim14 PRYSPRY substrate-recognition pocket with sub-micromolar affinity. Long-term DHQ treatment improves both nociceptive and affective symptoms by inhibiting spinal Trim14-JAK1-STAT3 axis in CIA mice. These findings suggest Trim14 as a potential neuroimmune target and DHQ as a natural medicine modulator for pain-depression comorbidity in chronic inflammatory disease.</p>

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Natural flavonoid dihydroquercetin blocks Trim14-JAK1-STAT3 signaling and relieves pain-depression comorbidity in rheumatoid arthritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Xiao-Wei Ni,
  • Bin Chai,
  • Zi-Meng Li,
  • Xin-Pei Li,
  • Chen Sun,
  • Xiao-Ling Yuan,
  • Ya-Bin Zhang,
  • Yan Zhang,
  • Wen-Juan Qian,
  • Hai-Long Zhang

摘要

Rheumatoid arthritis (RA) is frequently complicated by chronic pain, anxiety and depression, yet the neuroimmune mechanisms linking peripheral inflammation to central affective dysfunction remain elusive. Here we demonstrate that the natural flavonoid dihydroquercetin (DHQ) blocks Trim14 and relieves pain-depression comorbidity in RA. Serum Trim14 is elevated in RA patients and correlates with clinical symptom severity. We identify Trim14 as a contributing factor of JAK1/STAT3 signaling in spinal dorsal horn neurons, promoting both nociceptive sensitization and affective symptoms in collagen-induced arthritis (CIA) mice. Intrathecal Trim14 siRNA attenuates synovial inflammation, inflammatory pain and anxiety-depressive behaviors. Molecular docking and molecular dynamics simulations reveal that DHQ occupies the Trim14 PRYSPRY substrate-recognition pocket with sub-micromolar affinity. Long-term DHQ treatment improves both nociceptive and affective symptoms by inhibiting spinal Trim14-JAK1-STAT3 axis in CIA mice. These findings suggest Trim14 as a potential neuroimmune target and DHQ as a natural medicine modulator for pain-depression comorbidity in chronic inflammatory disease.