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<p>Lowering low‑density lipoprotein prevents many heart attacks, but not all. After decades of statins and proprotein convertase subtilisin/kexin type 9 inhibitors, residual cardiovascular risk remains high. This review argues that atherosclerosis (AS) is fundamentally a disease of lost cellular identity. We propose three testable hypotheses: (1) endothelium at low‑shear sites becomes epigenetically locked into a pro‑inflammatory state; (2) the dual face of vascular smooth muscle cell plasticity (repair vs. calcification) is determined by the duration of endoplasmic reticulum stress; (3) macrophage cholesterol retention and NOD‑like receptor family pyrin domain containing 3 activation form a self‑sustaining loop that explains why inflammation persists. We critically examine why most anti‑inflammatory trials have shown only modest benefits, and we identify three specific knowledge gaps that, if filled, would change clinical practice. By reframing AS as a problem of failed cellular identity, we offer a roadmap for mechanism‑based therapies.</p>

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Atherosclerosis revisited: integrating cellular plasticity, inflammatory circuits, and emerging therapeutic paradigms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Yifan Yang,
  • Ping Meng

摘要

Lowering low‑density lipoprotein prevents many heart attacks, but not all. After decades of statins and proprotein convertase subtilisin/kexin type 9 inhibitors, residual cardiovascular risk remains high. This review argues that atherosclerosis (AS) is fundamentally a disease of lost cellular identity. We propose three testable hypotheses: (1) endothelium at low‑shear sites becomes epigenetically locked into a pro‑inflammatory state; (2) the dual face of vascular smooth muscle cell plasticity (repair vs. calcification) is determined by the duration of endoplasmic reticulum stress; (3) macrophage cholesterol retention and NOD‑like receptor family pyrin domain containing 3 activation form a self‑sustaining loop that explains why inflammation persists. We critically examine why most anti‑inflammatory trials have shown only modest benefits, and we identify three specific knowledge gaps that, if filled, would change clinical practice. By reframing AS as a problem of failed cellular identity, we offer a roadmap for mechanism‑based therapies.