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<p>Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by dyslipidemia and characterized by foam cell formation originating from vascular smooth muscle cells (VSMCs). Mitophagy is a critical pathway for the selective clearance of dysfunctional mitochondria and also contributes to macrophage foaming. Tripartite motif-containing protein 65 (TRIM65), a key protein within the TRIM family, plays a significant role in immune and inflammatory responses and is integral to the pathogenesis of AS. In vivo and in vitro models of as were established using <i>ApoE</i><sup><i>−/−</i></sup> mice fed a high-fat diet and mouse aortic vascular smooth muscle (MOVAS) cells treated with oxidized low-density lipoprotein (ox-LDL), respectively. Results indicated a significant increase in TRIM65 expression in atherosclerotic models. The generation of <i>TRIM65</i><sup><i>−/−</i></sup><i>ApoE</i><sup><i>−/−</i></sup> mice demonstrated that TRIM65 knockdown reduced atherosclerotic plaque burden and lipid accumulation. In vitro experiments revealed that TRIM65 knockdown inhibited the formation of VSMC-derived foam cells while promoting mitochondrial autophagy. Mechanistic investigations showed that TRIM65 facilitates the degradation of key mitochondrial autophagy proteins (e.g., PINK1, Parkin), thereby inhibiting mitochondrial autophagy. This inhibition leads to the accumulation of dysfunctional mitochondria, resulting in excessive ROS generation and exacerbating oxidative stress. By inhibiting mitochondrial autophagy, TRIM65 accelerates the formation of VSMC-derived foam cells, thereby promoting the onset and progression of as. This discovery not only deepens our understanding of the molecular mechanisms of as but also provides theoretical support for positioning TRIM65 as a potential novel therapeutic target for the prevention and treatment of this disease.</p> Graphical abstract <p></p> <p>Under atherosclerotic stress conditions, <i>TRIM65</i><sup><i>–/–</i></sup><i>ApoE</i><sup><i>–/–</i></sup> mice and TRIM65-knockdown MOVAS cells exhibited elevated expression levels of key mitochondrial autophagy proteins, reduced ROS content, and efficient clearance of damaged mitochondria. This suppressed the transformation of smooth muscle cells into foam cells, thereby delaying the progression of atherosclerotic lesions.</p>

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TRIM65 accelerates VSMC-derived foam cell formation and arteriosclerosis progression by inhibiting mitophagy

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Liyuan Guo,
  • Wei Deng,
  • Zhixiang Zhou,
  • Qian Xu,
  • Kun Zhou,
  • Yuexin Zhang,
  • Yiyuan Bin,
  • Huiting Liu,
  • Zhong Ren,
  • Yisong Qian,
  • He Zheng,
  • Zhisheng Jiang

摘要

Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by dyslipidemia and characterized by foam cell formation originating from vascular smooth muscle cells (VSMCs). Mitophagy is a critical pathway for the selective clearance of dysfunctional mitochondria and also contributes to macrophage foaming. Tripartite motif-containing protein 65 (TRIM65), a key protein within the TRIM family, plays a significant role in immune and inflammatory responses and is integral to the pathogenesis of AS. In vivo and in vitro models of as were established using ApoE−/− mice fed a high-fat diet and mouse aortic vascular smooth muscle (MOVAS) cells treated with oxidized low-density lipoprotein (ox-LDL), respectively. Results indicated a significant increase in TRIM65 expression in atherosclerotic models. The generation of TRIM65−/−ApoE−/− mice demonstrated that TRIM65 knockdown reduced atherosclerotic plaque burden and lipid accumulation. In vitro experiments revealed that TRIM65 knockdown inhibited the formation of VSMC-derived foam cells while promoting mitochondrial autophagy. Mechanistic investigations showed that TRIM65 facilitates the degradation of key mitochondrial autophagy proteins (e.g., PINK1, Parkin), thereby inhibiting mitochondrial autophagy. This inhibition leads to the accumulation of dysfunctional mitochondria, resulting in excessive ROS generation and exacerbating oxidative stress. By inhibiting mitochondrial autophagy, TRIM65 accelerates the formation of VSMC-derived foam cells, thereby promoting the onset and progression of as. This discovery not only deepens our understanding of the molecular mechanisms of as but also provides theoretical support for positioning TRIM65 as a potential novel therapeutic target for the prevention and treatment of this disease.

Graphical abstract

Under atherosclerotic stress conditions, TRIM65–/–ApoE–/– mice and TRIM65-knockdown MOVAS cells exhibited elevated expression levels of key mitochondrial autophagy proteins, reduced ROS content, and efficient clearance of damaged mitochondria. This suppressed the transformation of smooth muscle cells into foam cells, thereby delaying the progression of atherosclerotic lesions.