Lu, QirongZhao, YongxiaXu, XiaoqingGuo, PuAres Lombán, IrmaMartínez Caballero, MartaLópez Torres, BernardoMartínez Larrañaga, María RosaAnadón Navarro, Arturo RamónPan, YuanhuWang, XuMartínez Caballero, María Aranzazu2025-10-172025-10-172025Lu, Q., Zhao, Y., Xu, X., Guo, P., Ares, I., Martínez, M., Lopez-Torres, B., Martínez-Larrañaga, M.-R., Anadón, A., Pan, Y., Wang, X., & Martínez, M.-A. (2025). Zaltoprofen and its novel analogues exhibit dual targeting of COX-2 and PPAR-γ, providing a strategy to alleviate lipopolysaccharide – induced acute lung injury. Biochemical Pharmacology, 242, 117420. https://doi.org/10.1016/j.bcp.2025.1174200006-295210.1016/j.bcp.2025.117420https://hdl.handle.net/20.500.14352/125071CRediT authorship contribution statement Qirong Lu: Writing – review & editing, Formal analysis, Methodology, Data curation, Investigation. Yongxia Zhao: Investigation, Writing – review & editing, Formal analysis, Methodology, Data curation. Xiaoqing Xu: Methodology, Data curation, Investigation, Writing – review & editing, Formal analysis. Pu Guo: Writing – review & editing, Formal analysis, Methodology, Data curation, Investigation. Irma Ares: Investigation, Writing – review & editing, Formal analysis, Methodology, Data curation. Marta Martínez: Methodology, Data curation, Investigation, Writing – review & editing, Formal analysis. Bernardo Lopez-Torres: Writing – review & editing, Formal analysis, Methodology, Data curation, Investigation. María-Rosa Martínez-Larranaga: ˜ Investigation, Writing – review & editing, Formal analysis, Methodology, Data curation. Arturo Anadon: ´ Writing – review & editing, Funding acquisition, Conceptualization, Writing – original draft, Formal analysis, Project administration, Data curation. Yuanhu Pan: Writing – original draft, Formal analysis, Project administration, Data curation, Writing – review & editing, Funding acquisition, Conceptualization. Xu Wang: Project administration, Data curation, Writing – review & editing, Funding acquisition, Conceptualization, Writing – original draft, Formal analysis. María-Aranzazu ´ Martínez: Project administration, Data curation, Writing – review & editing, Funding acquisition, Conceptualization, Writing – original draft, Formal analysis.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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1873-2968https://doi.org/10.1016/j.bcp.2025.11742041083023open access615.9Acute lung injuryDual targetCyclooxygenase-2Peroxisome proliferator-activated receptor-γZaltoprofenStrategyCiencias Biomédicas3214 Toxicología