RNA helicase MTR4 aggravates abdominal aortic aneurysm formation by recruiting SRSF1 to regulate TERT alternative...

Abdominal aortic aneurysm is a life-threatening vascular disease marked by the permanent, localized dilation of the abdominal aorta. Despite advances in understanding AAA pathogenesis, the molecular mechanisms, especially those related to aging, remain poorly understood. Alternative splicing, a pivotal regulatory mechanism, is notably dysregulated in abdominal aortic aneurysm. In our study, we employed a comprehensive approach, integrating splicing factor sequencing with AAA-specific bioinformatics analyses, to identify splicing factors influencing vascular smooth muscle cell (VSMC) aging. RNA helicase MTR4, caused a shift in TERT splicing to non-catalytic isoforms. Subsequent experiments unveiled a synergistic interaction between MTR4 and SRSF1, orchestrating the selective splicing of TERT. This interaction culminated in the production of non-catalytic TERT isoforms, which intriguingly exert anti-aging effects, independent of the canonical TERT enzymatic activity. Utilizing TERT splicing as a model splicing event in AAA may provide new insights into potentially targetable dysregulated splicing factors in VSMC aging related diseases.