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. 2021 Jan 11;11:430. doi: 10.1038/s41598-020-79948-x

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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PAI-1 inhibition triggers a lipid-lowering effect mediated by PCSK9 downregulation. As TM5614 inhibits PAI-1 activity, hepatic PCSK9 is downregulated at the transcriptional level (1). Consequently, plasma levels of PCSK9 decrease (2). Lower plasma PCSK9 levels exert a lower impact on catabolism of the LDL receptor (3), enabling the receptor to clear larger amounts of LDL-C from the circulation (4). The increase in intracellular cholesterol triggers the translocation of cholesterol sensing factors to the nucleus (5) to downregulate the transcription of genes involved in lipid metabolism (6). LRP-1, c-MET or FGFR/KlothoB are potential mediators for the observed effect. Animation created with https://biorender.com/.