New Strategy for Regulating Pyroptosis

A research team of scientists from the Traditional Chinese Medicine Biotechnology Production positions in the National Traditional Chinese Medicine Industry Technology System published a review article titled "Functional Materials Targeted Regulation of Gasdermins: From Fundamentals to Functionalities and Applications".

This study provided a systematic elucidation of the underlying mechanism of functional materials targeting Gasdermins, providing molecular design strategies to overcome corresponding shortcomings of the current immunotherapy, as well as offering important theoretical basis and practical guidance for the development of novel drugs used for immunotherapy.

The emergence of modern immunotherapy has completely changed the traditional treatment mode, and pyroptosis has become a hot topic in immune reprogramming research due to its unique mechanism of forming Gasdermin pore. The Gasdermin family is a group of proteins with sequence homology, which has garnered significant attention in recent years for their critical role as "executors" in pyroptosis. Under normal physiological conditions, the C-terminal domain of Gasdermins can inhibit the pyroptosis activity of the N-terminal domain. However, upon receiving a stimulus signal, the inflammasome may lyse Gasdermins, releasing N-terminal fragments and forming pore-like channels of varying sizes in the plasma membrane ultimately. In this context, it may trigger the release of cellular contents, causing local inflammatory and immune responses. All these processes have intimate association with the progression of inflammatory diseases and cancer. In this regard, how to precisely regulate the activity of these proteins has become the key to the treatment of inflammatory diseases, cancer and infectious diseases.

Gasdermin pore formation can be regarded as the core event of pyroptosis. For the first time, this research team identified Gasdermin pore formation, the event of "immune activation" prior to Gasdermin pore formation, and the event of "immune landscape remodeling" after Gasdermin pore formation as the three stages of pyroptosis, and elucidated pyroptosis from a completely new perspective. Innovatively, this study analyzed the interplay between pyroptosis and Gasdermin pore formation, followed by the summary and discussion on the structure, pore formation, and molecular events before and after Gasdermin pore formation. This study further dissected functional materials that directly regulated Gasdermin pore formation based on the therapy targeting pyroptosis, as well as functional materials that indirectly regulated molecular events before and after Gasdermin pore formation. Finally, this study comprehensively discussed the advantages, disadvantages, and future prospects of such functional materials from the laboratory to the pharmacy. Given the biological characteristics of Gasdermins, it may provide useful reference for the design of functional material-oriented precision therapies. It is anticipated to provide novel insights in design and optimization for researchers engaged in the development of precision therapies on the basis of the biological characteristics of Gasdermins in conjunction with functional materials.

This study not only comprehensively reviews the research progress in the field of pyroptosis, but also attached great attention to the exploration of the intrinsic relationship between pyroptosis and disease treatment. Simultaneously, in response to the existing bottleneck issues in this field, this study also proposes several directions for future research, including the need to develop personalized diagnosis and treatment plans based on individual patient characteristics and disease staging, the elucidation of filling in research gaps iconcerning the role of the Gasdermin family in some inflammatory diseases, and the requirement for considering interdisciplinary cooperation and multi-method application to combat drug resistance in the process of future drug design. All these efforts will exhibit important guiding significance for promoting clinical translation of therapeutic drugs targeting pyroptosis. Altogether, with the continuous advancement of molecular design and drug efficacy verification methods, therapeutic strategies targeting pyroptosis will develop progressively to drive immunotherapy into a new era.

The co-first authors of this study are doctoral student Tian Luyao and master's student Piao Shuo from the School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University. The corresponding authors are Professor Gao Wenyuan and Professor Li Xia from the School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, as well as Researcher Huang Luqi and Researcher Guo Lanping from the Chinese Academy of Traditional Chinese Medicine.

By School of Pharmaceutical Science and Technology

Editor: Sun Xiaofang