Fig. 3: TNF-induced necroptosis.

Necroptosis is a newly-described form of programmed cell death. Activating MLKL plays an important role in this process. The most widely studied subtype involves the TNF-inducible cell signal. In TNF-activated cells, RIPK1 is activated, and then activated RIPK1 forms complex IIb with RIPK3. MLKL is then phosphorylated by RIPK3 and recruited into the necrosome through interaction with RIPK3. By targeting organelles such as mitochondria and/or lysosomes, the cell membrane is destroyed, eventually leading to necrosis by cell lysis. LncRNA can regulate necroptosis by influencing this pathway. For example, the lncRNA NRF can directly downregulate miR-873, thereby reducing RIPK1/RIPK3 inhibition by miR-837, finally promoting necroptosis. In fibroblasts and macrophages, TLR3 or TLR4 interacts with RIPK3 through Total Recordable Incident Frequency (TRIF) to directly activate necrosis, independent from the RIPK1 signaling pathway. Cell swelling, mitochondrial dysfunction, membrane permeability, and cytoplasmic content release are observed.