时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
However, no STING inhibitors have yet been approved for clinical use, and none have advanced to clinical trials.；However, UNC9036 and SD02 exhibit molecular weights exceeding 1400 Da, a property that may compromise their drug-like profiles.；To date, however, only one molecular crowbar degrader has been reported, which targets Pin1 through covalent binding, leaving this mechanism largely unexplored for other proteins.
方法
To generate THP-1 cells expressing EGFP-STING, STINGN154S, or STINGV155M, THP-1-KO-STING cells were transduced with lentiviral plasmids encoding EGFP-STING-IRES-mCherry, STINGN154S, or STINGV155M, followed by selection with Puromycin (MeilunBio, MB2005-1).；STING-KO cells were validated by Western blot (Supplementary Fig. ).；After centrifugation (15,000 × g, 15 min, 4 °C), the supernatant protein concentration was quantified using a BCA assay kit (Thermo Fisher Scientific, 23225).；Western blot analysis was performed according to standard procedures.
核心结论
To identify STING degraders outperforming AK59 while minimizing potential false negatives due to the hook effect at higher concentrations, we selected 2 μM as the optimal screening concentration.；This screen identified several Oleanolic acid derivatives—including RTA 401, 402, dh404, 405, and 408—that markedly reduced STING protein levels (60%–97% reduction) at 2 μM, surpassing the performance of AK59 (Fig. and Supplementary Fig. ).；Notably, RTA 408, also known as Omaveloxolone, is an FDA-approved drug with a well-characterized safety profile, demonstrating obviously lower cytotoxicity than RTA 402 (Supplementary Fig. ). ‖ 结论：These results support Omaveloxolone’s potential utility as a therapeutic for aging-associated disorders and provide a critical preclinical foundation for expanding its clinical indications.
局限
While we provide experimental and computational evidence for Omaveloxolone’s binding and destabilizing effect on STING, the current lack of a high-resolution Omaveloxolone-STING complex structure represents a limitation of this study, and future structural biology efforts will be required to further define the precise binding mode.；Therefore, we cannot rule out the possibility that the in vivo protective effects of Omaveloxolone against aging-related inflammation may also be partially attributed to NRF2 activation.；This represents a limitation of the present study regarding the in vivo pharmacological mechanism.
对本项目的价值
★★☆☆☆ 炎症衰老是几乎所有慢性老年病的公共通路，也是最有希望做「抗炎但保留免疫」解耦的靶点。
全文来源
PMC JATS 全文（正文 70,882 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.
- 期刊与标识：Nat Commun · PMID 42957659 · DOI 10.1038/s41467-026-77760-1
B 级证据分级：B 级（同行评议临床前研究，主要为动物模型）
本文核心结论来自动物模型或体外细胞学，属临床前证据，不能外推至人体。「延长健康寿命」「改善功能」等表述在小鼠中的意义，与人类临床结局之间仍有距离。
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