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  3. Pseudane V alleviates ox-LDL-induced macrophage M1 polarization by inhibiting m6A modification of PPARGC1A

Pseudane V alleviates ox-LDL-induced macrophage M1 polarization by inhibiting m6A modification of PPARGC1A

  • Exp Cell Res. 2026 Jan 15;454(2):114842. doi: 10.1016/j.yexcr.2025.114842.
Tao Li 1,  Qi Pang 2,  Jun Pan 3,  Ya Gao 1,  Yuan Huang 1,  Wei Tian 4,  Junchuan Ran 1,  Zheng Zhu 1,  Yongbin Liu 1,  Kunsheng Li 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Lanzhou Petrochemical General Hospital (The Fourth Affiliated Hospital of Gansu University of Chinese Medicine), Lanzhou, 730060, China.
  • 2 Department of Traditional Chinese Medicine, Lanzhou Petrochemical General Hospital (The Fourth Affiliated Hospital of Gansu University of Chinese Medicine), Lanzhou, 730060, China.
  • 3 Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School (Nanjing Drum Tower Hospital Clinical College of Jiangsu University), Nanjing, 210008, China.
  • 4 The First Clinical Medical College, Graduate School of Gansu University of Chinese Medicine, Lanzhou, 730000, China.
  • 5 Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School (Nanjing Drum Tower Hospital Clinical College of Jiangsu University), Nanjing, 210008, China. Electronic address: [email protected].
PMID: 41297622 DOI: 10.1016/j.yexcr.2025.114842
Abstract

Atherosclerosis is driven by oxidized low-density lipoprotein (ox-LDL)-triggered macrophage malfunction, yet the precise pathways and effective counter-measures remain elusive. Here we delineated how N6-methyladenosine (m6A) RNA methylation governs ox-LDL-induced M1 macrophage polarization and evaluated Marine natural products for therapeutic intervention. Human monocytic THP-1 cells differentiated into M0 macrophages were treated with ox-LDL. M1/M2 polarization states were analyzed using flow cytometry, and changes in polarization markers were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Global m6A changes were detected using m6A dot blot and quantification analysis. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA Sequencing (RNA-seq) were performed to identify downstream target genes of the ox-LDL-m6A pathway. The role of Peroxisome Proliferator-activated Receptor gamma coactivator 1-alpha (PPARGC1A) in ox-LDL-induced M1 polarization was analyzed. A high-throughput marine natural product library was employed to discover agents capable of reversing ox-LDL-driven macrophage polarization. ox-LDL induces macrophage M1 polarization, and M1 macrophages damage endothelial cells. ox-LDL-induced polarization of macrophages into the M1 phenotype was associated with increased global RNA m6A modification. High levels of m6A modification induced by ox-LDL suppressed PPARGC1A expression in a YTH domain family 2 (YTHDF2)-dependent manner, leading to M1 polarization. Pseudane V, a marine natural product, effectively reduced ox-LDL-induced M1 polarization and protected vascular endothelial cells by correcting abnormal m6A modification of PPARGC1A. In conclusion, ox-LDL induces m6A modification of PPARGC1A, suppressing its expression and promoting M1 polarization of macrophages, contributing to atherosclerosis development. Pseudane V counteracts excessive m6A modification caused by ox-LDL, preventing M1 polarization of macrophages. These findings suggest the potential use of Pseudane V in preventing atherosclerosis.

Keywords

Atherosclerosis; Macrophage; PPARGC1A; Pseudane V; m(6)A.

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