2. Academic Validation
  3. Zaltoprofen and its novel analogues exhibit dual targeting of COX-2 and PPAR-γ, providing a strategy to alleviate lipopolysaccharide - induced acute lung injury

Zaltoprofen and its novel analogues exhibit dual targeting of COX-2 and PPAR-γ, providing a strategy to alleviate lipopolysaccharide - induced acute lung injury

  • Biochem Pharmacol. 2025 Dec;242(Pt 4):117420. doi: 10.1016/j.bcp.2025.117420.
Qirong Lu 1,  Yongxia Zhao 2,  Xiaoqing Xu 2,  Pu Guo 3,  Irma Ares 4,  Marta Martínez 4,  Bernardo Lopez-Torres 4,  María-Rosa Martínez-Larrañaga 4,  Arturo Anadón 5,  Yuanhu Pan 6,  Xu Wang 7,  María-Aránzazu Martínez 4
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Animal Nutrition and Feed Science, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan 430023, China.
  • 2 National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
  • 3 Hubei Key Laboratory of Animal Nutrition and Feed Science, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan 430023, China; National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
  • 4 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain.
  • 5 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain. Electronic address: [email protected].
  • 6 National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Hubei 430070, China. Electronic address: [email protected].
  • 7 National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Hubei 430070, China. Electronic address: [email protected].
PMID: 41083023 DOI: 10.1016/j.bcp.2025.117420
Abstract

Acute lung injury (ALI) is a multi-system and multifactorial disease, which is characterised by an uncontrolled inflammatory response and high mortality. Zaltoprofen (ZPF), is a non-steroidal anti-inflammatory drug (NSAID) with powerful anti-inflammatory effects, as well as an analgesic action on inflammatory pain. Therefore, this research study aims to explore whether ZPF, its main metabolite M2 (S-oxide-zaltoprofen) and novel analogues can alleviate ALI through multiple targets. Based on molecular docking, the similar topological structure binding properties of protein targets (STSBPT) strategy, the cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS), for first time, this study found that cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-γ (PPAR-γ) are dual targets of ZPF and M2. Based on this outcome, novel analogues related to ZPF and M2 were designed. The present research study also examined the effect and the cellular and molecular mechanisms of ZPF, M2 and the novel analogues on LPS-induced ALI in vitro and in vivo, through the dual targets of COX-2 and PPAR-γ. The findings of this study suggest that the STSBPT strategy could assist as a probable multi-target medicinal drug screening strategy, and ZPF, its main metabolite M2 and its novel analogues could serve as potential therapeutic agents for the treatment of ALI, through the both COX-2 and PPAR-γ molecular signalling targets.

Keywords

Acute lung injury; Cyclooxygenase-2; Dual target; Peroxisome proliferator-activated receptor-γ; Strategy; Zaltoprofen.

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