Fig. 3: Molecular mechanisms of PCD in ECs during sepsis.
From: Research advances on the role of programmed endothelial cell death in sepsis
In sepsis, endothelial pattern recognition receptors—TLRs sensing PAMPs (LPS, etc.) and TNFRs sensing circulating cytokines (TNF-α, IL-1β, IL-18)—trigger distinct PCD pathways. Apoptosis is initiated by either the mitochondrial route (BAX/BAK-mediated MOMP, antagonized by BCL-2/BCL-xL) or the death-receptor route (ligand-activated TNFR/FAS recruiting FADD, DISC, and caspase-8), culminating in the activation of irreversible caspase cascades. Pyroptosis follows inflammasome assembly: NLRP3 senses ox-mtDNA, mtROS, and NF-κB signaling, assembling with ASC and pro-caspase-1 to generate inflammatory caspases that cleave GSDMD-N, forming membrane pores and releasing inflammation factors. When caspase-8 is inhibited, necroptosis ensues via RIPK1/RIPK3 necrosome assembly and MLKL phosphorylation, producing membrane pores. Ferroptosis is driven by iron-dependent lipid peroxidation: transferrin delivers Fe2⁺, system Xc⁻ imports cystine for GSH synthesis, and GPX4-mediated detoxification of PUFA-OOH. Loss of GPX4 or GSH accumulation of PUFA-OH propagates Fenton chemistry, yielding lethal membrane damage. IAPs, SMAC, and cIAPs modulate caspase activity and final cell fate.
