Naringenin ameliorates collagen‐induced arthritis through activating AMPK‐mediated autophagy in macrophages

BACKGROUND: Naringenin is widely recognized for its notable attributes, including anti‐inflammatory, anti‐cancer, and immunomodulatory activities. However, its specific implications for rheumatoid arthritis (RA) and the underlying mechanisms remain to be explored. This study aimed to investigate the therapeutic efficacy and pharmacological mechanism of Naringenin in the treatment of collagen‐induced arthritis (CIA). METHODS: A CIA model was established in DBA/1 mice, and various doses of Naringenin were administered orally to assess its impact on RA. The study also involved lipopolysaccharides (LPS)‐induced RAW264.7 cells to further evaluate the effects of Naringenin. Mechanistic studies were conducted to elucidate the signaling pathways involved in Naringenin's actions. RESULTS: Naringenin significantly alleviated foot inflammation in DBA/1 CIA mice and attenuated the levels of pro‐inflammatory cytokines in serum. It also enhanced antioxidant capacity in the CIA model. In vitro studies with LPS‐induced RAW264.7 cells demonstrated that Naringenin attenuated pro‐inflammatory cytokines and reactive oxygen species (ROS) levels. Mechanistic studies confirmed that Naringenin activated autophagy and increased autophagic flux. Blocking autophagy, either by silencing Atg5 or inhibiting autophagolysosome using chloroquine, effectively counteracted the impact of Naringenin on pro‐inflammatory cytokines. Further exploration revealed that Naringenin activated the AMPK/ULK1 signaling pathway, and inhibition of AMPK reversed the initiation of autophagy and reduced pro‐inflammatory cytokine secretion induced by Naringenin. CONCLUSIONS: This study unveils a novel mechanism by which Naringenin may be used to treat RA. It demonstrates the therapeutic efficacy of Naringenin in a CIA model by reducing inflammation, modulating cytokine levels, and enhancing antioxidant capacity. Moreover, the activation of autophagy through the AMPK/ULK1 signaling pathway appears to play a critical role in Naringenin's anti‐inflammatory effects. These findings suggest potential strategies for the development of anti‐rheumatic medications based on Naringenin.