Natural products in rheumatoid arthritis: Cell type-specific mechanisms and therapeutic implications

The pathogenesis of rheumatoid arthritis (RA) involves abnormal activation and interactions among various cell types. Traditional Chinese medicine (TCM) natural products show therapeutic potential with multi-target anti-inflammatory effects, but their specific impacts on RA-related cell types remain unclear.

This review aims to provide a comprehensive overview of the effects of natural products on key cell types in RA.

We extensively searched PubMed, Web of Science, and Scopus until April 2025, using keywords like "natural products," "rheumatoid arthritis," "cellular mechanisms," and specific cell types. Studies on natural products' effects on RA-related cells were included and analyzed.

This review marks the first attempt to integrate cellular resolution in evaluating therapeutic mechanisms of natural products in RA. The key findings highlight the cell-type-specific effects and mechanistic underpinnings of natural products. Sinomenine preferentially inhibits fibroblast-like synoviocytes (FLS) proliferation via toll-like receptor 4 (TLR4) /MyD88/NF-κB blockade, whereas icariin reprograms macrophage polarization through ERK/HIF-1α/GLUT1 signaling pathway. Besides, natural products exhibit shared mechanisms across different cell types, such as oxidative stress and inflammatory pathway regulation. Importantly, certain natural products exhibit pan-cellular effects, targeting multiple cell types involved in RA pathogenesis. For example, resveratrol acts on a wide range of cell types including FLS, human umbilical vein endothelial cells (HUVECs), T cells, osteoclasts, chondrocytes, macrophages, monocytes, osteoblasts, and neutrophils.

Through an in-depth analysis of cellular mechanisms, this work highlights the specific regulatory effects of natural products on key cell types and their extensive influence across cellular networks. By examining these effects at the cellular level, this review establishes a new framework for developing novel RA therapeutics with increased cell selectivity, thus advancing precision phytomedicine and translational research.