Figure. NINJ1 regulates plasma membrane fragility under mechanical strain

Supported by the National Natural Science Foundation of China (grant no. 32371199, 82070311, 82270274, 82250610229), Professor Jie Xu and Associate Professor Fuli Xiang from the First Affiliated Hospital of Sun Yat-sen University, in collaboration with Assistant Professor Zheng Shi from Rutgers University, have made significant progress in understanding plasma membrane rupture (PMR) induced by mechanical force. Their study, titled “NINJ1 regulates plasma membrane fragility under mechanical strain,” was published online in Nature on June 9, 2025 (Article link: https://www.nature.com/articles/s41586-025-09222-5).

The plasma membrane acts as a cellular barrier that helps maintaining cell homeostasis. Under mechanical stress, such as compression, shear flow, or tissue stretching, the membrane may rupture, releasing intracellular contents (including DNA, organelles, and inflammatory molecules) and triggering strong immune responses. This phenomenon, known as plasma membrane rupture (PMR), is not only a common terminal event in various cell death pathways but also a trigger for immune activation, tissue damage, and even cytokine storms. However, what determines the membrane ruptures under high mechanical stress? Are there specific regulatory factors response in such extreme stress? Several key scientific issues in this field remain unresolved.

In this study, the researchers developed a novel high-throughput screening system capable of applying precise, reproducible mechanical strain to cells. Using this system, they screened 10,843 siRNAs targeting 2,726 multi-pass transmembrane proteins, and monitored changes in plasma membrane permeability during the application of mechanical strain. They identified that NINJ1 was a critical regulator of mechanically induced membrane rupture and this process occurs independent of programmed cell death pathways. Further investigation revealed that NINJ1 levels on the plasma membrane were inversely correlated with the mechanical force required for rupture. However, NINJ1 alone is insufficient to cause complete rupture, and an additional mechanical force is still necessary to induce full PMR.

By integrating mechanical and electronic engineering, biophysics, mechanobiology, and high-throughput genetic screening, this study identified NINJ1 as a key membrane protein modulating plasma membrane fragility. Unlike conventional mechano-sensitive ion channels or G protein–coupled receptors, NINJ1 functions at a fundamental physical-structural level to regulate mechanical responses. Clinically, NINJ1 may represent a new therapeutic target for conditions involving mechanical stress-related tissue injury, excessive inflammation, or autoimmune diseases. Moreover, the high-throughput mechanical stimulation system developed in this study could be utilized to screen other mechano-sensitive genes, aiding the discovery of potential drugs for related diseases.