Zhiwang decoction inhibits the inflammatory response and macrophage polarization in rheumatoid arthritis by mediating...

Zhiwang Decoction (ZWD) is a classical traditional Chinese medicine formulation with documented efficacy in alleviating the clinical manifestations of RA, yet its precise molecular mechanisms are not fully defined.

To evaluate the anti-inflammatory and protective effects of ZWD in RA and to elucidate its potential mechanisms of action, with a focus on the role of cellular communication network factor 1 (CCN1) and macrophage polarization.

A multi-level investigative approach was adopted, utilizing a collagen-induced arthritis (CIA) rat model, lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, and human synovial tissues from RA and osteoarthritis (OA) patients. The therapeutic effects of ZWD were systematically assessed, and its mechanism was explored by analyzing CCN1 expression, macrophage M1 polarization, and the PI3K/AKT pathway.

ZWD administration significantly attenuated arthritis severity and systemic inflammation in CIA rats. Mechanistic studies revealed that CCN1 was overexpressed in RA synovium and correlated positively with inflammatory activity. In vitro, CCN1 inhibition suppressed LPS-induced PI3K/AKT phosphorylation, inflammatory cytokine production, and M1 macrophage polarization. Notably, ZWD treatment downregulated CCN1 expression, inhibited PI3K/AKT pathway activation, and reduced inflammatory responses and M1 macrophage proportion in both animal and cellular models.

ZWD exerts anti-RA effects by mitigating inflammation and suppressing M1 macrophage polarization. These therapeutic actions are mechanistically linked to the inhibition of the CCN1-dependent PI3K/AKT pathway.