Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated -PGE2 biosynthesis by sonlicromanol's metabolite KH176m

Increased prostaglandin E2 (PGE(2)) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta)-induced PGE(2) production in control skin fibroblasts. Comparable results were obtained in the mouse macrophagelike cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammationinduced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE(2)-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.

Automated summary

Increased levels of PGE(2) were detected in patient cells with mitochondrial disease, but were normalized by exposure to KH176m. This redox-modulator also selectively inhibited PGE(2) production in control skin fibroblasts, suggesting potential therapeutic applications for mitochondrial disease and beyond.