2. Academic Validation
  3. Ophiopogonin D reprograms the polarization of macrophages through modulating PPM1K-mediated branched-chain amino acids catabolism to delay atherogenesis

Ophiopogonin D reprograms the polarization of macrophages through modulating PPM1K-mediated branched-chain amino acids catabolism to delay atherogenesis

  • Int Immunopharmacol. 2026 May 15:177:116551. doi: 10.1016/j.intimp.2026.116551.
Shangmin Yu 1,  Jiaqi Liu 2,  Shan Liu 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutics, School of Pharmacy, Bengbu Medical University, Bengbu 233000, Anhui, China. Electronic address: [email protected].
  • 2 School of Clinical Medicine, Bengbu Medical University, Bengbu 233000, Anhui, China. Electronic address: [email protected].
  • 3 Department of Physiology, School of Basic Medicine, Bengbu Medical University, Bengbu 233000, Anhui, China. Electronic address: [email protected].
PMID: 41871493 DOI: 10.1016/j.intimp.2026.116551
Abstract

Background: Atherosclerosis (AS) is a chronic inflammatory vascular disease. Macrophage reprogramming plays a crucial role in the progression of AS. Ophiopogonin D (OP-D), a bioactive constituent of Ophiopogon japonicus, has exhibited potent anti-atherosclerotic property. However, whether OP-D exerts its atheroprotective effect via reprogramming macrophage remains unclear. This study aimed to investigate the effect of OP-D on AS and elucidate its underlying mechanism.

Methods: The atheroprotective effect of OP-D on atherosclerotic mice was evaluated by histological and molecular assays. The crucial role of macrophage in OP-D's atheroprotective effect was detected by flow cytometry and verified through macrophage depletion/infusion. The direct effect of OP-D on macrophages were assessed in vitro by RT-qPCR, flow cytometry, and immunofluorescence. RNA Sequencing and amino acid-targeted metabolomics analysis were employed to identify the associated amino acid metabolic pathways. In addition, PPM1K deficient was established to validate the role of branched-chain Amino acids (BCAAs) in macrophage reprogramming and OP-D's therapeutic effect.

Results: Our results demonstrated that OP-D attenuated the progression of AS and directly prevented the M1-like polarization of macrophages. Meanwhile, the therapeutic benefits of OP-D were abolished after macrophages depletion, suggesting macrophage was a crucial mediator of OP-D's therapeutic effect. Further mechanistic studies revealed that dysregulated BCAAs metabolism-mediated macrophage polarization underlay the anti-atherosclerotic effect of OP-D.

Conclusion: This study elucidated that OP-D reprogrammed the polarization of macrophages through modulating BCAAs catabolism to delay atherogenesis. These findings will deepen the understanding of OP-D's atheroprotective mechanisms and provide a potential therapeutic target for AS.

Keywords

Branched-chain amino acids catabolism; Macrophage; Ophiopogonin D; Polarization; Vascular inflammation.

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