2. Academic Validation
  3. Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes

Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes

  • Bioorg Chem. 2026 Aug 5:177:109925. doi: 10.1016/j.bioorg.2026.109925.
Yang Zhang 1,  Jie Guo 2,  Jie Jin 3,  Ci-An Cheng 4,  Yixin Hu 5,  Shihao Chen 6,  Chen Wang 7,  Xinwei Meng 7,  Binglu Jiang 8,  Zhihao Jia 9,  Yixue Qiao 10,  Jinxin Gu 11,  David A Tyvoll 12,  James P Collman 13,  Lei Fu 14
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
  • 2 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 3 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 4 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 5 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 7 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China.
  • 8 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 9 Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 10 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 11 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 12 Department of Chemistry, Stanford University, Stanford, CA, USA. Electronic address: [email protected].
  • 13 Department of Chemistry, Stanford University, Stanford, CA, USA. Electronic address: [email protected].
  • 14 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China; Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China. Electronic address: [email protected].
PMID: 42070307 DOI: 10.1016/j.bioorg.2026.109925
Abstract

Mitohormesis, an adaptive cellular response to moderate mitochondrial stress, represents a promising therapeutic paradigm. To pharmacologically harness this phenomenon, we developed mitochondrial respiration inhibitors by conjugating a thiazole-based pharmacophore to a triphenylphosphonium (TPP) cation. Here, we report three TPP-thiazole conjugates which are distinguished by their hydrolytically labile linkers, comprising an ester (Compound 1), a more labile thioester (Compound 2), and a more stable amide (Compound 3). In vitro evaluation demonstrated that the hydrolytic stability of the linkers correlated inversely with inhibitory potency, where Compound 2 exhibited the strongest inhibition, followed by Compound 1. In contrast, Compound 3 showed negligible activity, lacking a clear dose-response relationship. As therapeutic mitohormesis requires a mild stress induction within a beneficial hormetic window, Compound 1 was selected for further investigation based on its intermediate inhibition and pronounced biphasic effects. Compound 1 activated the mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans (C. elegans) and stimulated transcription of mitokines in both C. elegans and mice. In a murine model of diet-induced type 2 diabetes, Compound 1 significantly improved systemic metabolism, ameliorating glucose intolerance, Insulin resistance, and hepatic steatosis. Furthermore, it outperformed metformin at an equivalent dose without observed toxicity. Collectively, these findings establish the rationally tuned inhibition of mitochondria as a viable small-molecule strategy for the treatment of metabolic disorders through mitohormesis.

Keywords

Metabolic disorders; Mitochondria; Mitohormesis; TPP-thiazole; UPR(mt).

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