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

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.