Abstract
Transthyretin is a tetrameric transport protein whose monomers, when destabilized, can misfold and form amyloid fibrils, leading to serious diseases like transthyretin amyloidosis cardiomyopathy and neuropathy. While kinetic stabilisers such as tafamidis or acoramidis are designed to prevent tetramer dissociation, clinical data show a puzzling increase in TTR levels after treatment—an effect that our study seeks to investigate by exploring possible underlying mechanisms. Using a simple phenomenological model, we explore whether reduced dissociation alone accounts for this rise or if other mechanisms contribute. We propose that stabilisers may alter TTR clearance by slowing its cellular internalisation or degradation, or even by influencing its synthesis through pharmacological chaperoning. We also examine the role of monomer removal from circulation via re-association into tetramers or through other, possibly pathogenic processes. By integrating pharmacokinetic and pharmacodynamic data with experimental observations, our model provides fresh insights into TTR homeostasis and offers testable predictions for future research. This study highlights the power of simplified, hypothesis-driven models in uncovering biological mechanisms—or, at the very least, in identifying key questions that remain to be answered.
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All data generated or analysed during this study are included in this published article and its supplementary information files.
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Funding
This research was co-funded by the European Union within the VITAL Horizon Europe project (Grant nr 101136728). BL and VB are supported by a grant from the Priority Research Area qLIFE under the Strategic Programme Excellence Initiative at Jagiellonian University under the agreement 06/IDUB/2019/94. VB acknowledges the support of UNCE, project number UNCE/24/MED/008 and the project New Technologies for Translational Research in Pharmaceutical Sciences / NETPHARM, project ID CZ.02.01.01/00/22_008/0004607, co-funded by the European Union.
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BL, SU and SP conceived the study and designed the model. BL performed the simulations. BL, SU, VB analysed the data. BL, SU, VB, BW contributed to data interpretation and visualization. BL and SU wrote the first draft of the manuscript. All authors reviewed and approved the final version of the manuscript.
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Lisowski, B., Ulaszek, S., Wiśniowska, B. et al. Phenomenological model of transthyretin stabilization. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35000-y
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DOI: https://doi.org/10.1038/s41598-026-35000-y
