Adapalene, an RAR agonist, exerts anti-inflammatory effects by regulating macrophage polarization through RAR[Formula: see text]-mediated signaling pathways.

Retinoic acid receptor (RAR) is a nuclear receptor that plays a critical role in regulating cellular proliferation and differentiation through transcriptional control. However, its role in the macrophage inflammatory response remains poorly understood. In the present study, we explored the effects of adapalene, a selective RARβ and RARγ agonist, on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. Adapalene inhibited the LPS-induced inflammatory response in a concentration-dependent manner, whereas the anti-inflammatory effects of adapalene were attenuated by RARβ-targeting small interfering RNA (siRNA) or an RARβ antagonist (LE135). Mechanistic investigations revealed that adapalene suppressed LPS-induced phosphorylation of the MAPK and PI3K/Akt pathways, thereby inhibiting the nuclear translocation of NF-κB in RAW264.7 cells. In addition, adapalene upregulated the expression of anti-inflammatory M2 macrophage markers, accompanied by increased STAT3 phosphorylation. The acute administration of adapalene to C57BL/6J mice protected against LPS-induced inflammation, liver damage, and septic shock-related mortality in vivo. Furthermore, chronic oral administration of adapalene in high-fat diet (HFD)-induced obese mice reduced pro-inflammatory markers while increasing anti-inflammatory markers in the liver. These findings suggest that adapalene exerts potent anti-inflammatory effects in macrophages through RARβ activation, thus highlighting its potential as a therapeutic agent for treating inflammatory and metabolic disorders.