Fenchone attenuates CD68-dependent 7-ketocholesterol accumulation, cholesterol dyshomeostasis and inflammatory responses via modulation of macrophage polarization

This study elucidates the pharmacologic efficacy of fenchone in mitigating foam cell formation by modulating cholesterol homeostasis, inflammatory signaling and polarization in macrophages.

Murine IC-21 macrophages were induced with 7KCh and co-treated with fenchone. Cell viability was assessed using alamar blue assay, while lipid and calcium accumulation were analyzed with oil red O and alizarin red S staining. Pinocytosis, phagocytosis and actin cytoskeleton were evaluated with neutral red, goat RBCs uptake and phalloidin, respectively. Molecular changes were determined using ELISA, flow cytometry, PCR, western blot and in silico docking.

Fenchone significantly inhibited lipid and calcium accumulation, reduced lipid peroxidation and restored homeostatic endocytosis with anti-inflammatory cytoskeleton. It enhanced anti-inflammatory TGFβ1 and Smad2/3 while suppressing pro-inflammatory NF-κB, IL-1β, IL-6 and TNF-α. In addition, fenchone regulated cholesterol homeostasis via ABCA1, ApoE, LXR, CD36 and promoted M2 polarization by increasing CD163 and CD206 markers, downregulating M1 markers (CD38, CD68 and CD86). Computational analysis indicated the interactive affinity of 7KCh toward the CD68 scavenger receptor, which was prevented by fenchone.

These findings highlight the therapeutic potential of fenchone in managing atherosclerosis by targeting CD68-mediated 7KCh uptake and inflammatory cascade, thereby emerging as a potential pharmacotherapeutic agent in inflammatory diseases.

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