Figure 2. Mechanisms of AICD. (IMAGE)
Caption
The excessive accumulation of extracellular ATP might serve as a trigger signal to activate purinergic receptors, particularly P2X7R, whereas disruption of ATP homeostasis may contribute to energy impairment or organelle stress. P2X7R stimulation can lead to Ca²⁺ influx, K⁺ efflux, enhanced membrane permeability, and ionic dysregulation, while PANX1-mediated membrane permeabilization may further contribute to downstream inflammatory and cell death-related signaling. Mitochondrial dysfunction and ROS generation, together with impaired NADPH-supported glutathione- and thioredoxin-dependent antioxidant buffering, endoplasmic reticulum (ER) stress, and NLRP3 inflammasome activation, may also contribute to inflammatory signaling amplification and damage to the plasma membrane, leading to cellular injury that may relate to outcomes including apoptosis, pyroptotic cell death, necrosis, ferroptosis, or mixed types of cell death. In turn, cellular injury and death can also trigger ATP release, generating an ATP release-mediated amplification loop. The figure summarizes the various possible relationships between AICD-related abnormalities, cellular stress, and multiple cell death types. It does not mean that all molecular events take place in a deterministic order, that disruption of ATP homeostasis directly activates P2X7R, or that all cell death outcomes result from the same general ATP‐P2X7R signaling pathway.
Credit
Doblin Sandai, Wangzheqi Zhang, Xiaokun Li and Hao Pan / Medicine Discovery
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