Artemisinin derivative SM934 targets α-enolase to inhibit PEP-mediated TAK1 stabilization and inflammation.

TGF-β-activated kinase 1 (TAK1) is a key signaling hub and drug target in inflammatory responses. Although metabolism has been critically linked to immune cell function and inflammation, the metabolic control of TAK1 activation and intervention strategy remains to be explored. Here, we show that SM934, a derivative of the traditional Chinese medicine artemisinin, inhibits inflammatory responses via targeting α-enolase and inhibiting metabolite phosphoenolpyruvate (PEP) production. PEP directly binds TAK1 and inhibits its ubiquitination at the lysine-72 site, which promotes NF-κB activation and inflammatory responses. Overall, our study demonstrates a metabolic control of TAK1 stabilization and proposes that it could be disrupted by the derivative of the natural product artemisinin.