Iguratimod suppresses volume-sensitive outwardly rectifying anion channels via arachidonic acid accumulation

Iguratimod, an anti-rheumatic agent, is known to suppress the production of inflammatory cytokines and inhibit B-cell proliferation. Recent studies have implicated volume-sensitive outwardly rectifying (VSOR) Cl^- channels in the regulation of immune responses. In this study, we investigated whether iguratimod modulates VSOR Cl^- currents using whole-cell patch-clamp recordings in human embryonic kidney 293T cells. Iguratimod inhibited hypotonicity-induced VSOR Cl^- currents in a concentration-dependent manner. Notably, celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, also significantly suppressed these currents. Furthermore, pyrrophenone, a phospholipase A₂ inhibitor, attenuated the inhibitory effect of iguratimod on VSOR Cl^- currents. Under hypotonic conditions, the levels of free arachidonic acid were significantly elevated in the presence of iguratimod and celecoxib. These findings suggest that iguratimod increases free arachidonic acid levels by inhibiting COX-2 during osmotic cell swelling, thereby suppressing VSOR Cl^- channel activity. This suppression of VSOR Cl^- channel activity may present one of the mechanisms through which iguratimod exerts its anti-inflammatory effects in rheumatic diseases.