cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy

Nov 7, 2022Experimental neurology

cGAS-STING pathway may worsen early brain injury after blood flow returns by triggering ferritin breakdown through NCOA4 in mice

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

NCOA4-mediated ferritinophagy is linked to increased brain injury following cerebral ischemia-reperfusion.

Cerebral ischemia-reperfusion injury (CIRI) may be aggravated by an imbalance in iron metabolism.
Activation of NCOA4-mediated ferritinophagy at the early stage of cerebral ischemia-reperfusion is associated with oxidative stress, autophagy, and apoptosis.
Inhibition of the cGAS-STING pathway reduces ferritinophagy, oxidative stress, autophagy, and apoptosis in a mouse model of CIRI.
Overexpression of NCOA4 reverses the protective effects of cGAS-STING pathway inhibition, suggesting its role in exacerbating CIRI.

AI simplified

Stroke patients are often complicated by cerebral ischemia-reperfusion injury (CIRI) after the restoration of cerebral perfusion, and how to prevent CIRI at an early stage has received close attention. The imbalance of iron metabolism is one of the essential factors in the aggravation of CIRI, and NCOA4-mediated ferritinophagy, as a critical pathway to regulate iron metabolism, is expected to be an effective intervention target. We established a mouse model of cerebral ischemia-reperfusion (CIR) with NCOA4 silencing. We found that activation of NCOA4-mediated ferritinophagy atthe early stage of CIR mediated the onset of oxidative stress and contributed to autophagy and apoptosis, and eventually resulted in increased brain injury. This suggests that NCOA4-mediated ferritinophagy plays a vital role in early CIR and can be an effective target to prevent and treat CIRI. We next explored the upstream regulatory targets of NCOA4-mediated ferritinophagy. The previous evidence for the cGAS-STING pathway's importance during CIR and its strong relationship with autophagy attracted our attention. To investigate whether the cGAS-STING pathway regulates NCOA4-mediated ferritinophagy, we further administered a cGAS inhibitor to mice with CIR and overexpressed NCOA4. Along with the inhibition of the cGAS-STING pathway, ferritinophagy, oxidative stress, autophagy, and apoptosis were inhibited, and CIRI was ameliorated, which was attenuated by NCOA4 overexpression. In conclusion, our results suggest that activation of the cGAS-STING pathway exacerbates CIRI at the early stage of CIR, which may be achieved by mediating NCOA4-mediated ferritinophagy.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief