Quantifying the underlying landscape, entropy production and biological path of the cell fate decision between apoptosis and pyroptosis

Abstract

Pyroptosis, a recently identified type of cell death, and apoptosis are fundamental and complex biological processes that underlie a multitude of diseases. However, the crosstalk between pyroptosis and apoptosis, as well as their molecular regulatory mechanisms governing decision-making, remain to be fully elucidated. In particular, comprehending how internal driving forces, including vital components of life such as proteins and reactions, collaborate with the environment to dictate cell fate remains an ongoing challenge. To address these issues, a cell death decision module model of the crosstalk between pyroptosis and apoptosis was developed. Stability analysis revealed the presence of three steady-state attractors within the death decision system: the apoptosis state attractor, the pyroptosis state attractor, and the concurrence state attractor. Landscape theory was employed to study the stochastic dynamic and global stability of the death decision system, allowing us to quantitatively describe the uncertainty of cell death decisions by measuring the production of Shannon entropy. In addition, we identified the dominant kinetic paths among different death mode attractors. We found that the dominant kinetic paths between different cell death modes usually do not pass through the minimum potential point. Through quantifying the underlying driving force of the system's dynamics, we determined that this phenomenon is attributed to the dependence of the driving force in non-equilibrium systems on both the gradient force and the curl force. In summary, this study offers a natural and physical groundwork for understanding the crosstalk network between pyroptosis and apoptosis, providing valuable insights and therapeutic strategies for the regulation of cell death modes in mammals.