2. Academic Validation
  3. Design and synthesis of protoberberine analogues to alleviate LPS-induced acute lung injury by targeting HCK and blocking the HCK-NLRP3 axis

Design and synthesis of protoberberine analogues to alleviate LPS-induced acute lung injury by targeting HCK and blocking the HCK-NLRP3 axis

  • Eur J Med Chem. 2025 Oct 8;302(Pt 1):118252. doi: 10.1016/j.ejmech.2025.118252.
Tianyun Fan 1,  Guanjun Li 2,  Huiying Li 1,  Liting Xu 2,  Yuting He 2,  Ruishen Zhuge 2,  Wenhua Kuang 2,  Lirun Zhou 2,  Jiangpeng Wu 3,  Yinghong Li 4,  Yali Song 5,  Jigang Wang 6
Affiliations

Affiliations

  • 1 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
  • 2 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
  • 3 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: liyinghong@imb.pumc.edu.cn.
  • 5 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China. Electronic address: syl@smu.edu.cn.
  • 6 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China; Department of Critical Medicine, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518020, China. Electronic address: jgwang@icmm.ac.cn.
PMID: 41118702 DOI: 10.1016/j.ejmech.2025.118252
Abstract

Acute lung injury (ALI) is associated with high morbidity and mortality, but its effective treatment is lacking. Here, we synthesized 71 protoberberine derivatives, of which 35 were new, and evaluated their anti-inflammatory activity in LPS-induced RAW264.7 cells. Compound 2d showed a decent potency in reducing not only nitric oxide (NO) level with the IC50 value of 6.52 μM, but also multiple pro-inflammatory cytokine levels, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. Meanwhile, it alleviated the historical damages in lung and decreased TNF-α, IL-1β and IL-6 levels in serum and lung tissue on LPS-induced ALI in mice. Using activity-based protein profiling technology, we found that 2d directly targeted Hck protein, and subsequently diminished the expression of NLRP3, ASC, pro-caspase-1 and pro-IL-1β in both LPS-induced RAW264.7 cells and ALI murine model. Therefore, we consider protoberberine derivatives to be a promising class of anti-ALI agents, and Hck to be a key target of these compounds in the treatment of NLRP3 related inflammatory diseases.

Keywords

Acute lung injury; HCK; NLRP3; Protoberberine derivatives; Structure−activity relationship.

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