2. Academic Validation
  3. Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway

Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway

  • Biochem Pharmacol. 2026 Apr:246:117708. doi: 10.1016/j.bcp.2026.117708.
Hongbo Wang 1,  Zihao Wen 1,  Yupeng Jia 1,  Xinyu Tong 2,  Weifang Wang 1,  Ze Wang 1,  Hongkai Jin 2,  Xiaoya Gao 3,  Xinyuan Tao 4,  Hao Cheng 5,  Tingting Li 5,  Shinan Li 1,  Tingting Chen 6,  Kunfang Li 7,  Bo Li 8
Affiliations

Affiliations

  • 1 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China; College of Basic Medical Science, Jinzhou Medical University, Jinzhou 121001, China.
  • 2 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China.
  • 3 School of Nursing, Jinzhou Medical University, Jinzhou 121001, China.
  • 4 First Clinical Medicine School of Jinzhou Medical University, Jinzhou 121001, China.
  • 5 School of Software, Shenyang Technical College, Shenyang 110033, China.
  • 6 School of Basic Medicine, Guangdong Medical University, Dongguan 523808, China. Electronic address: [email protected].
  • 7 College of Basic Medical Science, Jinzhou Medical University, Jinzhou 121001, China. Electronic address: [email protected].
  • 8 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China; College of Basic Medical Science, Jinzhou Medical University, Jinzhou 121001, China. Electronic address: [email protected].
PMID: 41544858 DOI: 10.1016/j.bcp.2026.117708
Abstract

AACOCF3, a cell-permeable arachidonic acid analogue, is widely established as a selective inhibitor of cytosolic Phospholipase A2 (cPLA2, PLA2G4A) in studies of metabolic disorders. Although its primary mechanism involves cPLA2 inhibition, emerging evidence indicates that AACOCF3 may target additional protein entities, exemplified by calcium-independent Phospholipase A2 (iPLA2, PLA2G6) and fatty acid amide hydrolase (FAAH). Notably, cPLA2 displays a markedly heterogeneous expression profile in non-small cell lung Cancer (NSCLC). Our findings establish that AACOCF3 exerts more potent growth inhibition in cPLA2-negative NSCLC cells, with IC50 values of 15.13 μM for H1975 and 15.84 μM for PC9 cells, in contrast to the cPLA2-positive A549 cells (IC50 = 56.23 μM). Mechanistically, AACOCF3 upregulates IFN-α/β signaling-associated genes (e.g., IFNB1, ISG15) specifically in cPLA2-negative NSCLC cells. This aligns with TCGA-LUAD data revealing that PLA2G4A-low tumors predominantly engage immune-activation pathways rather than metabolic programs when compared to PLA2G4A-high counterparts. Through integrated molecular docking and surface plasmon resonance (SPR) analysis, we identified structure-specific recognition protein 1 (SSRP1) as a direct molecular target of AACOCF3 in cPLA2-negative NSCLC, with SPR binding studies confirming a stable interaction (Kd = 25.9 μM). Ectopic SSRP1 expression abrogated AACOCF3-induced phenotypic alterations, concurrently suppressing IFN-α/β signaling. Collectively, these results provide evidence that AACOCF3 exerts its anti-proliferative effect by targeting SSRP1, which leads to the activation of the IFNα/β pathway, thereby underscoring its therapeutic promise for the cPLA2-negative patient subpopulation.

Keywords

AACOCF3; IFNα/β signaling; NSCLC; SSRP1; cPLA2.

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