Context-dependent mTOR pharmacology in atherosclerotic plaque stability and exposure-guided modulation
- 1Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Health Science Center, Hunan Normal University
- 2Health Management Center, Hengyang Central Hospital Affiliated to Hunan Normal University
- 3Aging Health Research Center, School of Nursing, Health Science Center, Hunan Normal University
Abstract
Despite advances in lipid lowering, anti-inflammatory therapy and revascularization, residual cardiovascular risk may partly reflect persistent lesion-level inflammation and defective plaque repair that are not fully corrected by systemic risk-factor control. The mechanistic target of rapamycin (mTOR) integrates inflammatory, metabolic and reparative programmes, but its effects vary with cell state, plaque niche, complex identity, and signalling amplitude and duration. Evidence is strongest for context-dependent macrophage mTOR signalling, yet macrophage/myeloid mTORC2 disruption has produced opposing lesion phenotypes across genetic models; endothelial and smooth-muscle evidence remains less direct. Pharmacological, genetic and lesion-directed delivery studies demonstrate that mTOR perturbation can modify experimental atherosclerosis. However, genetic perturbation cannot be equated with rapalog pharmacology, and existing studies do not yet define cell-resolved exposure–engagement–response relationships and relate them to plaque composition. This evidential asymmetry limits interpretation of whether broad or prolonged mTOR inhibition can selectively suppress disease-amplifying outputs while preserving homeostatic programmes. In this Review, focused primarily on lipid-rich, rupture-prone plaques and using rapalogs as the principal pharmacological model, we apply an exposure-guided pharmacological framework to distinguish administered dose from lesion exposure, cellular availability, target engagement and pharmacodynamic recovery. Compartment-resolved PK–PD studies, cell-specific pathway interrogation and large-animal validation will be needed to quantify these relationships and determine whether maladaptive mTOR outputs can be suppressed without compromising vascular repair.
Related
- Task-Dependent Modulation of Upper-Extremity Muscle Synergies during Object Slippage
- Behavioral ontogeny in a pelagic tunicate reveals developmental maturation and context-dependent modulation
- Structural basis for the CsrA-dependent modulation of translation initiation by an ancient regulatory protein.
- MSC-derived extracellular vesicles for spinal cord injury: inflammatory microenvironment modulation, stage-dependent repair mechanisms, and translational challenges
- Xylazine Reshapes the Sleep and Respiratory Consequences of Chronic Fentanyl Exposure in a Sex-Dependent Manner
BibTeX
@article{han2026contextdependent,
title = {{Context-dependent mTOR pharmacology in atherosclerotic plaque stability and exposure-guided modulation}},
author = {Ruoyu Han and Mao Peng and Zihang Song and Yifan Tang and Ziyi Yao and Yan She and Shuhan Cheng and Xiaomin Li and Pingping He},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1994231},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1994231/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Context-dependent mTOR pharmacology in atherosclerotic plaque stability and exposure-guided modulation
AU - Ruoyu Han
AU - Mao Peng
AU - Zihang Song
AU - Yifan Tang
AU - Ziyi Yao
AU - Yan She
AU - Shuhan Cheng
AU - Xiaomin Li
AU - Pingping He
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1994231
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1994231/full
AB - Despite advances in lipid lowering, anti-inflammatory therapy and revascularization, residual cardiovascular risk may partly reflect persistent lesion-level inflammation and defective plaque repair that are not fully corrected by systemic risk-factor control. The mechanistic target of rapamycin (mTOR) integrates inflammatory, metabolic and reparative programmes, but its effects vary with cell state, plaque niche, complex identity, and signalling amplitude and duration. Evidence is strongest for context-dependent macrophage mTOR signalling, yet macrophage/myeloid mTORC2 disruption has produced opposing lesion phenotypes across genetic models; endothelial and smooth-muscle evidence remains less direct. Pharmacological, genetic and lesion-directed delivery studies demonstrate that mTOR perturbation can modify experimental atherosclerosis. However, genetic perturbation cannot be equated with rapalog pharmacology, and existing studies do not yet define cell-resolved exposure–engagement–response relationships and relate them to plaque composition. This evidential asymmetry limits interpretation of whether broad or prolonged mTOR inhibition can selectively suppress disease-amplifying outputs while preserving homeostatic programmes. In this Review, focused primarily on lipid-rich, rupture-prone plaques and using rapalogs as the principal pharmacological model, we apply an exposure-guided pharmacological framework to distinguish administered dose from lesion exposure, cellular availability, target engagement and pharmacodynamic recovery. Compartment-resolved PK–PD studies, cell-specific pathway interrogation and large-animal validation will be needed to quantify these relationships and determine whether maladaptive mTOR outputs can be suppressed without compromising vascular repair.
SN - 1663-9812
ER -