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  3. Covalently targeting HSP90 with a natural small-molecule costunolide to inhibit necroptosis and ulcerative colitis

Covalently targeting HSP90 with a natural small-molecule costunolide to inhibit necroptosis and ulcerative colitis

  • Int Immunopharmacol. 2026 Apr 1:174:116348. doi: 10.1016/j.intimp.2026.116348.
Shan Yang 1,  Yunsen Zhang 2,  Yuying Shi 3,  Ting Liu 3,  Jingjing Tian 4,  Shuai Tan 4,  Xianli Meng 5,  Wuzheng Luo 6,  Xiaofei Shen 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; Institute of High Altitude Multimorbidity/TCM-Integrated High-Altitude Medicine Center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
  • 2 Theoretical and Computational Biophysics Group, NIH Resource for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana 61820, IL, USA.
  • 3 TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
  • 4 Department of Traditional Chinese Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China.
  • 5 Institute of High Altitude Multimorbidity/TCM-Integrated High-Altitude Medicine Center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. Electronic address: [email protected].
  • 6 Department of Traditional Chinese Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China.. Electronic address: [email protected].
  • 7 TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. Electronic address: [email protected].
PMID: 41687519 DOI: 10.1016/j.intimp.2026.116348
Abstract

Background: Necroptosis exacerbates ulcerative colitis (UC) by disrupting intestinal barriers and promoting necroinflammation. Heat shock protein 90 (HSP90) regulates receptor-interacting protein kinase 1/3 (RIPK1/3) activity through its chaperone function, thereby participating in Necroptosis and emerging as a potential therapeutic target for its inhibition in UC therapy. Costunolide (CTL), a principal sesquiterpene lactone from Aucklandia lappa, has poorly defined mechanisms in UC treatment. This study aimed to elucidate CTL's role in Necroptosis inhibition and UC therapy by targeting HSP90.

Methods: Multiple cellular models were employed to assess CTL's inhibitory effects on Necroptosis and necroinflammation. Subsequently, western blotting and co-immunoprecipitation (Co-IP) were used to analyze the impact of CTL on Necroptosis signaling. Functional targets and binding sites of CTL were identified through drug affinity responsive target stability (DARTS), mass spectrometry, and cellular thermal shift assay (CETSA). Molecular dynamics simulation and tryptophan quenching were then conducted to elucidate CTL-mediated allosteric regulatory mechanisms. In vivo, dextran sulfate sodium (DSS)-induced colitis mice were used to evaluate the therapeutic efficacy of CTL.

Results: CTL is identified as a novel Necroptosis inhibitor that suppresses RIPK1/3-mixed lineage kinase domain-like protein (MLKL) signaling and mitigates necroinflammation in vitro. Mechanistically, CTL covalently binds to the conserved cysteine (Cys) 572/564 in the middle domain of HSP90, inhibiting its dimerization and chaperone function via an allosteric effect without significantly compromising ATPase activity or triggering substantial heat shock response. This covalent interaction further disrupts HSP90-RIPK1 association, consequently blocking RIPK1/3-MLKL Necroptosis signaling. In vivo, CTL is capable of effectively alleviating DSS-induced colitis via blocking RIPK1/3-MLKL axis activation.

Conclusion: Our findings highlight Cys572/564 as a druggable site for allosteric HSP90 inhibition and propose that CTL acts as a promising chemical scaffold for developing therapeutics targeting necroptosis- and HSP90-driven pathologies, such as UC.

Keywords

Colitis; Costunolide; Covalent binding; HSP90; Necroptosis.

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