Fig. 4

Molecular signaling pathway of pyroptosis in age-related macular degeneration. A Priming of NLRP3 with TLR. B Activation of the NF‑κB pathway induces the transcription of NLRP3 and pro‑IL‑1β. C–H Components of drusen activate the NLRP3 inflammasome. C Ox-LDL can induce a large amount of ROS, targeting the CD36 receptor, thereby causing lysosomal disruption following cathepsin release, or promoting the ATP/P2X7R/Ca²⁺ influx pathway to activate NLRP3. D Complement components: C1Q initiates lysosomal rupture and release of cathepsin B to activate NLRP3 assembly, while C5a and C3 send priming signals to NLRP3 without a clear mechanism. E, F Aβ1-40 increases intracellular ROS via NOX4 and mitochondrial electron transport chain to activate NLRP3. G Aβ1-40 acts as a priming signal to activate the NF-κB pathway, which upregulates the transcription of NLRP3, pro-IL-18, and pro-IL-1β. H MicroRNAs: miR-191-5p is downregulated after Aβ1-40 stimulation, subsequently leading to an increase in C/EBPβ levels, resulting in the upregulation of NLRP3; miR-223 and miR-22-3p suppress NLRP3 expression. I Alu RNA due to DICER1 deficiency increases ROS production; Alu RNA-induced NF-κB-mediated NLRP3 activation and P2X7R signaling control NLRP3 inflammasome priming and activation, respectively. J ATP outflow via connexin43 hemichannels acts as a NLRP3 inflammasome signal 2 activator. K A2E, a major fluorophore in lipofuscin, activates NLRP3 by causing lysosomal damage and release of cathepsins into the cytoplasm. L Membrane attack complex (MAC) deposition triggers the assembly and activation of the NLRP3 inflammasome downstream of the Aβ1-40 priming signal. M The mature form of IL-18 mediates the activation of interleukin-1 receptor-associated kinases 1 and 4 (IRAK1 and IRAK4), which contributes to RPE cell death