https://doi.org/10.1016/j.apsb.2026.06.042
This new article publication from
Acta Pharmaceutica Sinica B discusses the discovery of the covalent inhibitor A12 and the identification of DNAJC9 as a potential drug target for sepsis-associated inflammation.
Excessive inflammation contributes to organ injury in sepsis, creating a need for new approaches to control the dysregulated immune response. Natural products offer starting points for drug discovery, but their activity and molecular targets often require further investigation. The authors of this article modified tanshinone IIA, a compound found in the medicinal plant Salvia miltiorrhiza, by introducing a chemical group designed to form a covalent bond with a target protein. Screening and structural optimization identified A12, which showed approximately 100-fold greater anti-inflammatory activity than the parent compound and inhibited inflammatory cytokine release at submicromolar concentrations in cell experiments. Oral administration of A12 reduced TNF-α, IL-6, and IL-12 in a lipopolysaccharide-induced mouse model of acute systemic inflammation, while additional experiments showed reduced lung and intestinal injury. A12 also extended the survival window in a cecal ligation and puncture mouse model of sepsis. Using chemical probes and proteomic analysis, the researchers identified DNAJC9, a co-chaperone in the heat shock protein system, as a direct target. Further experiments showed that A12 forms a covalent bond at DNAJC9’s cysteine 243 residue. Reducing DNAJC9 expression also suppressed inflammatory cytokines and diminished the additional effect of A12, supporting the target’s role in the compound’s activity. The findings link DNAJC9 modulation to nuclear accumulation of HSP70 and suppression of NF-κB inflammatory signaling, although the detailed mechanism requires further investigation. This research identifies a previously unrecognized role for DNAJC9 in inflammation and establishes A12 as a lead compound for further development. The evidence comes from cell and animal studies; its safety and efficacy in people remain to be established. The proposed application is control of sepsis-associated acute inflammation alongside treatment of the underlying infection.
Keywords: Tanshinone derivatives, Covalent inhibitor, Proteomic analysis, Target identification, DNAJC9, HSP complex, Anti-inflammatory, Sepsis
Graphical Abstract: available
https://ars.els-cdn.com/content/image/1-s2.0-S2211383526003990-ga1_lrg.jpg
Tanshinone derivatives covalently bind DNAJC9, modulating HSP complex and reducing inflammation, enabling novel sepsis treatment.
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The Journal of the
Institute of Materia Medica, the Chinese Academy of Medical Sciences and the
Chinese Pharmaceutical Association.
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CiteScore: 24.4
Impact Factor: 14.6 (Top 8 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 14.0
ISSN 2211-3835
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Xingjun Li, Tao Yang, Hui Huang, Yalan Ma, Lu Liu, Qingqing Li, Naixia Zhang, Zhizhen Hui, Yazhou Li, Fang Bai, Qiangqiang Chen, Jiang Wang, Chen Zhou, Hu Zhou, Wei Tang, Hong Liu, Discovery of a potent covalent inhibitor for the treatment of sepsis targeting DNAJC9: Identification of a druggable target for inflammation, Acta Pharmaceutica Sinica B, Volume 16, Issue 10, 2026, Pages 6892–6904, ISSN 2211-3835,
https://doi.org/10.1016/j.apsb.2026.06.042