2. Academic Validation
  3. Novel BLT1 inhibitor baeckein E ameliorates LPS-induced acute lung injury through ferroptosis inhibition

Novel BLT1 inhibitor baeckein E ameliorates LPS-induced acute lung injury through ferroptosis inhibition

  • Phytomedicine. 2026 Jun:155:158147. doi: 10.1016/j.phymed.2026.158147.
Yahui Mi 1,  Rong Wang 1,  Jianqiang Qian 1,  Zhaojing Liu 1,  You Li 1,  Hairan Fan 1,  Lu Wang 1,  Haimin Kuai 1,  Fei Xiong 2,  Hao Wang 3,  Xinhong Shi 4,  Xiaolong Hu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, China.
  • 3 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 41966024 DOI: 10.1016/j.phymed.2026.158147
Abstract

Background and purpose: Acute lung injury (ALI) currently lacks targeted pharmacological therapies. Baeckein E, a natural compound from Baeckea frutescens l., has demonstrated anti-inflammatory and anti-lipid peroxidation properties. While the anti-inflammatory role of the leukotriene B4 receptor 1 (BLT1) is recognized, our preliminary data reveal a novel function in inhibiting Ferroptosis. This study aims to investigate the hypothesis that baeckein E confers protection against ALI by targeting BLT1, thereby attenuating both inflammation and Ferroptosis.

Experimental approach: To evaluate the bioactivity of baeckein E, we established a RAW264.7 inflammation model to assess its anti-inflammatory effects, alongside MLE-12 models of inflammation-induced Ferroptosis and direct Ferroptosis to analyze its anti-ferroptosis properties. Furthermore, the therapeutic efficacy of baeckein E was investigated in an in vivo ALI mouse model induced by intratracheal LPS instillation. Photoaffinity labeling assay was performed to identify the direct binding target of baeckein E. Immunofluorescence and Co-immunoprecipitation analyses were conducted to examine the downstream signaling of BLT1. A BLT1-knockdown cell model was utilized to verify the target specificity of baeckein E.

Key results: In the RAW264.7 inflammation model, baeckein E significantly suppressed inflammatory cytokine production. Parallelly, in MLE-12 models of Ferroptosis, baeckein E potently inhibited lipid peroxidation and promoted Nrf2 nuclear accumulation alongside GPX4 transcription. In the murine ALI model, baeckein E treatment attenuated pulmonary macrophage infiltration, enhanced the GSH/GSSG ratio, and upregulated GPX4 protein expression. Mechanistic investigations identified BLT1 as the direct target of baeckein E, through which it concurrently suppresses the macrophage MyD88/NF-κB pathway and activates the epithelial cAMP/Nrf2 axis, ultimately blocking Ferroptosis. The essential role of BLT1 was confirmed by RNA knockdown experiments.

Conclusion and implications: Our study demonstrates that baeckein E alleviates ALI by targeting BLT1 to suppresses inflammation-driven Ferroptosis both directly and indirectly. These findings not only elucidate a dual-mechanism of action for baeckein E but also substantiate BLT1 as a new promising therapeutic target for treating ferroptosis-related diseases.

Keywords

Acute lung injury; Anti-ferroptosis; Anti-inflammatory; BLT1; Baeckein E.

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