Fisetin Attenuates Human Macrophage Polarization and Pro‐Inflammatory Responses via NLRP3 and NF‐κB/MAPK Suppression

ABSTRACT

Natural compounds with anti‐inflammatory properties are increasingly explored as therapeutic agents due to their lower risk of side effects compared with conventional drugs. Fisetin, a dietary bioflavonol abundant in fruits and vegetables, exhibits anti‐inflammatory activity in several cell types, including murine macrophages. However, its effects on human macrophages remain unclear. In this study, human pro‐inflammatory M1 macrophages were generated from THP‐1 monocytes using PMA, LPS, and IFN‐γ. The effects of fisetin on cytokine and chemokine secretion, reactive oxygen species (ROS) production, apoptosis, and phagocytic activity were evaluated. In addition, the NF‐κB, MAPK, and NLRP3 inflammasome pathways were analyzed. This study shows that fisetin pre‐treatment significantly suppressed LPS/IFN‐γ‐induced secretion of pro‐inflammatory cytokines (IL‐6, TNF‐α, IL‐1β, IL‐8) and chemokines (MCP‐1, CCL5, CXCL9, CXCL10). It also reduced ROS generation, NLRP3 inflammasome activation, and phagocytic activity. Mechanistically, fisetin inhibited NF‐κB activation as well as JNK/MAPK and p38/MAPK signaling, indicating that its anti‐inflammatory actions are mediated through multiple pathways. Importantly, fisetin did not affect the viability or proliferation of THP‐1‐derived macrophages, suggesting that reduced cytokine release was primarily due to attenuation of macrophage polarization rather than cytotoxicity. Fisetin attenuates inflammatory responses in human M1 macrophages through suppression of NF‐κB, MAPK, and NLRP3 inflammasome signaling. By limiting cytokine release, ROS production, and phagocytic activity without impairing cell survival, fisetin emerges as a promising natural candidate for managing chronic inflammatory disorders, including atherosclerosis, neurodegenerative diseases, and inflammatory bowel disease.