Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation

Abstract Aberrant activation of the STING signaling pathway is involved with aging-related inflammation, yet no STING-targeting therapeutics are clinically approved. Here, we identify Omaveloxolone, an FDA-approved drug for Friedreich’s ataxia, as a potent STING degrader (DC 50 = 118 nM, D max = 98.6%) via high-throughput screening. Omaveloxolone binds non-covalently to the base of the STING ligand-binding domain (LBD) with high affinity ( K D = 21.4 nM) and exhibits crowbar-like behavior consistent with STING conformational destabilization: it hinders LBD closure, increases hydrophobic exposure, and reduces thermal stability. This conformational perturbation is proposed to enhance recognition by the E3 ubiquitin ligase HUWE1, leading to K27-linked ubiquitination at STING lysines K236/K347/K370 and proteasomal degradation. In vivo, Omaveloxolone depletes STING, suppresses downstream inflammatory signaling, and ameliorates aging-related inflammatory phenotypes in aged male mice. Because Omaveloxolone is also an established NRF2 activator, these in vivo benefits likely reflect dual modulation of inflammatory and antioxidant pathways. This study implicates Omaveloxolone as a molecular crowbar-like STING degrader and provides a mechanistic framework for targeting STING via conformational perturbation.