2. Academic Validation
  3. SJB2-043, a USP1 Inhibitor, Suppresses A549 Cell Proliferation, Migration, and EMT via Modulation of PI3K/AKT/mTOR, MAPK, and Wnt Signaling Pathways

SJB2-043, a USP1 Inhibitor, Suppresses A549 Cell Proliferation, Migration, and EMT via Modulation of PI3K/AKT/mTOR, MAPK, and Wnt Signaling Pathways

  • Curr Issues Mol Biol. 2025 Feb 27;47(3):155. doi: 10.3390/cimb47030155.
Lipeng Wu 1,  Meng Yu 1,  Huosheng Liang 2,  Long Lin 1,  Huajian Li 1,  Guangyang Chen 1,  Halimulati Muhetaer 1,  Jingjing Li 3,  Bo Wu 1,  Xuejing Jia 4,  Yuanye Dang 1,  Guodong Zheng 1,  Chuwen Li 1
Affiliations

Affiliations

  • 1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou 510645, China.
  • 2 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
  • 3 Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong 999077, China.
  • 4 College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
PMID: 40136409 DOI: 10.3390/cimb47030155
Abstract

Objective: Non-small cell lung Cancer (NSCLC) remains one of the most significant contributors to cancer-related mortality. This investigation explores the influence and underlying mechanisms of the USP1 Inhibitor SJB2-043 on A549 cells, with the aim of advancing the development of anti-NSCLC therapeutics.

Methods: Publicly available databases were utilized to assess USP1 expression and its association with the progression of NSCLC. Gene expression variations were ascertained through RNA Sequencing, followed by the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway enrichment evaluations. Various doses of SJB2-043 were administered to A549 cells to evaluate its impact on cell multiplication, motility, Apoptosis, and the cell cycle using CCK-8 assays, colony formation, wound healing, flow cytometry, and Western blotting (WB).

Results: USP1 was found to be overexpressed in NSCLC specimens and linked to adverse prognosis. Treatment with SJB2-043 markedly inhibited A549 cell proliferation and migration, diminished clonogenic potential, and triggered Apoptosis in a dose-dependent manner. Modifications in the cell cycle were observed, showing an elevated percentage of cells in the G2 phase while exhibiting a parallel decline in the G1 phase. WB examination demonstrated diminished protein levels of N-Cadherin, CyclinB1, CDK1, c-Myc, Bcl-2, p-ERK/ERK, p-p38/p38, p-JNK/JNK, p-AKT/Akt, and p-mTOR/mTOR, alongside an upregulation of E-cadherin, ZO-1, occludin, p53, Bax, p-β-catenin/β-catenin, and GSK3β.

Conclusions: SJB2-043 exerts a suppressive effect on A549 cell proliferation, migration, and epithelial-mesenchymal transition while enhancing Apoptosis. These cellular effects appear to be mediated through the inhibition of the MAPK, Wnt/β-catenin, and PI3K/Akt/mTOR signaling cascades, in addition to modulation of the cell cycle.

Keywords

SJB2-043; USP1 inhibitor; epithelial–mesenchymal transition (EMT); non-small cell lung cancer (NSCLC).

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