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bioRxiv · 10.1101/2025.09.23.677952

NPAS2 attenuates VSMC phenotypic switching in ascending thoracic aortic aneurysm via LPCAT3/PC-PUFA2S-mediated ferroptosis

Lin, W.·Xiong, J.·Yan, Y.·Bian, J.·Zhang, Z.·Xu, X.·Diao, Y.·Lan, X.·Zhong, Y.·Ji, H.·Shao, Y.·Ni, B.
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Abstract

Ascending thoracic aortic aneurysm (ATAA) is a life-threatening disorder with limited therapeutic options, critically linked to vascular smooth muscle cell (VSMC) phenotypic switching. Neuronal PAS Domain Protein 2 (NPAS2), a circadian rhythm-related transcription factor, regulates diverse physiological processes. However, the biological functions and underlying regulatory mechanisms of NPAS2 in VSMCs during ATAA pathogenesis remain to be elucidated. NPAS2 expression decreased in ATAA patients, PDGF-BB-treated HASMCs and BAPN-administrated mice. NPAS2 depletion facilitated VSMC phenotype switching. VSMC-specific NPAS2 knockout (NPAS2SMKO) mice exhibited aggravated ATAA. Mechanistically, NPAS2 depletion attenuates its transcriptional repression of LPCAT3, subsequently elevating the accumulation of phosphatidylcholines with two polyunsaturated fatty acyl chains (PC-PUFA2S), thereby promoting ferroptosis-induced VSMC phenotype switching and accelerating ATAA progression. Targeting NPAS2 represents a potential therapeutic strategy for ATAA treatment.

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Lin, W., Xiong, J., Yan, Y., Bian, J., Zhang, Z., Xu, X., Diao, Y., Lan, X., Zhong, Y., Ji, H., Shao, Y., Ni, B.. 2025-09-25. NPAS2 attenuates VSMC phenotypic switching in ascending thoracic aortic aneurysm via LPCAT3/PC-PUFA2S-mediated ferroptosis. https://doi.org/10.1101/2025.09.23.677952

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