For a long time, cell necrosis was regarded as a passive "accident" caused by energy depletion. However, recent studies have found that some forms of necrosis, such as necroptosis, are regulated by precise signaling pathways-a kind of "programmed explosion."
Classic Programmed Necrosis Pathway (Left Side of Notes):
When the death signal TNF-α binds to its receptor TNFR, it recruits and activates RIPK1 and RIPK3, forming the "necrosome." Subsequently, MLKL is phosphorylated (P-MLKL) and translocates to the cell membrane, forming pores like a "hole puncher." This causes a massive influx of calcium (Ca²⁺), sodium (Na⁺), and water, leading to osmotic imbalance, swelling, and eventual rupture of the cell.
Crosstalk with the Inflammatory Storm (Right Side of Notes):
Before cell rupture, danger signals such as HMGB1, K⁺, and H₂O₂ activate the NLRP3 inflammasome, which recruits and activates Caspase-1. Caspase-1, on one hand, cleaves inactive Pro-IL-1β and Pro-IL-18 into mature pro-inflammatory factors; on the other hand, it cleaves the GSDMD protein. The N-terminal fragment of GSDMD inserts into the cell membrane to form pores, releasing IL-1β and IL-18 and triggering a cascade-amplified inflammatory response (pyroptosis).
Pathological Significance and Clinical Implications:
This violent form of death releases DAMPs (damage-associated molecular patterns). While it helps clear pathogens, it often becomes an accomplice in diseases such as ischemia-reperfusion injury, neurodegenerative diseases, and inflammatory diseases like gout.
Currently, specific inhibitors targeting RIPK1, MLKL, GSDMD, and NLRP3 are under development. In the future, precisely blocking these "explosion switches" may provide new targets for treating inflammation- and necrosis-related diseases.