PANoptosis (泛凋亡)

PANoptosis is a novel pathway of inflammatory programmed cell death (PCD) that integrates key molecular components and phenotypic features from three major pathways-pyroptosis, apoptosis, and necroptosis-and is specifically regulated by the PANoptosome complex. PANoptosis involves extensive crosstalk and cannot be blocked by inhibiting any single pathway alone. PANoptosis exerts host-protective effects in anti-infective and anti-tumor contexts, while mediating pathological damage in cases of excessive inflammation, cytokine storms, and organ injury.
The PANoptosome complex responds to stimuli such as infection and cellular stress; it is organized into three functional layers-sensor, adaptor, and effector proteins-and, upon activation, simultaneously triggers membrane rupture, the release of cellular contents, and the secretion of inflammatory cytokines. Currently, four distinct subtypes of the PANoptosome complex have been identified: ZBP1 (which recognizes Z-RNA), AIM2 (which recognizes dsDNA), RIPK1 (which responds to intracellular bacterial infections), and NLRP12 (which responds to hemolytic events). All four subtypes are dependent on transcriptional regulation by IRF1 and are negatively regulated by factors such as ADAR1. The core components of the four PANoptosis subtypes are as follows^[1]:
1. ZBP1-PANoptosome contains: ZBP1 (sensor), NLRP3, ASC, caspase-1/6/8, RIPK1/3.
2. AIM2-PANoptosome contains: AIM2 (sensor), Pyrin, ZBP1, ASC, caspase-1/8, RIPK1.
3. FADD-RIPK1-PANoptosome contains: RIPK1 (sensor), RIPK3, NLRP3, ASC, and Caspase-1/8.
4. NLRP12-PANoptosome contains: NLRP12 (sensor), ASC, Caspase-8, and RIPK3.