Aberrant STING activation promotes macrophage senescence by suppressing autophagy in vascular aging from diabetes

Area of Science:

• Cellular senescence
• Vascular biology
• Immunometabolism

Background:

• Diabetic vascular aging is a significant complication of diabetes mellitus.
• Macrophage senescence and its associated secretory phenotype (SASP) contribute to vascular dysfunction.
• The role of STING in macrophage senescence in diabetes remains unclear.

Purpose of the Study:

• To investigate the role of STING in macrophage senescence in the context of type 2 diabetes.
• To elucidate the molecular mechanisms linking STING, autophagy, and senescence in diabetic vascular aging.
• To evaluate the therapeutic potential of targeting the STING-autophagy axis.

Main Methods:

• Utilized a type 2 diabetes mellitus mouse model (streptozotocin and high-fat diet).
• Assessed vascular aging markers and senescent macrophages *in vivo* and *in vitro*.
• Investigated the STING-autophagy pathway by examining ULK1 phosphorylation and using pharmacological modulators (H-151, DMXAA).

Main Results:

• High glucose induced macrophage senescence, which in turn promoted senescence in co-cultured vascular smooth muscle cells.
• STING activation was found to inhibit autophagy by phosphorylating ULK1 at S757, thereby accelerating senescence.
• Pharmacological inhibition of STING (H-151) reduced senescence, while STING agonism (DMXAA) enhanced it.

Conclusions:

• The STING-autophagy axis is a critical driver of macrophage senescence in diabetic vascular aging.
• STING activation promotes senescence by suppressing autophagy via ULK1 phosphorylation.
• Targeting the STING-autophagy pathway presents a promising therapeutic strategy for mitigating diabetic vascular complications.