The identification of a form of necrosis mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL) has led to a significant breakthrough that has fundamentally transformed our understanding of necrosis. Traditionally viewed as uncontrolled cell death, necrosis is now perceived differently in various human diseases due to this discovery.¹

Recent research suggests that necroptosis is a common mechanism of retinal cell death, alongside apoptosis. While the clinical manifestations and pathogenesis of retinal diseases differ, they share similar necroptotic signalling pathways. Inhibition of necroptosis offers promising neuroprotective effects for the treatment of various retinal degenerative disorders.¹

A study focussed on the role of necroptosis in retinal diseases and injuries. The review covered the main molecules involved in the necroptosis of retinal cells and their inhibitors that could help in the development of new therapeutic strategies for the management of retinal degenerative diseases. ¹

Figure 1. Molecular mechanisms of necroptosis¹

Adapted from: Zhang Q, et al. Int J Biol Sci. 2023.

A20: TNF-α-induced protein 3; ABIN1: A20-binding inhibitor of NF-κB; Casp-8: Caspase-8; cFLIP: Cellular FLICE-like inhibitory protein; cIAP1/2: Cellular inhibitor of apoptosis proteins 1 and 2; CYLD: Cylindromatosis; DAMP: Damage-associated molecular pattern; DNA: Deoxyribonucleic acid; DRP1: Dynamin-related protein 1; ESCRT-III: Endosomal sorting complexes III; FADD: Fas-associated protein with death domain; IKK: IκB kinase; LUBAC: Linear ubiquitin chain assembly complex; MLKL: Mixed-lineage kinase domain-like pseudokinase; NEMO: NF-κB essential modulator; NF-κB: Nuclear factor kappa B; OPTN: Optineurin; PARP: Poly-ADP ribose polymerase; PGAM5: Phosphoglycerate mutase family member 5; RIPK: Receptor-interacting protein kinase; ROS: Reactive oxygen species; SPATA2: Spermatogenesis associated protein 2; TAK1: Transforming growth factor beta-activated kinase 1; tAIF: Truncated apoptosis-inducing factor; TBK1: TANK-binding kinase 1; TBK2/3: TAK1- binding protein 2/3; TNFα: Tumour necrosis factor alpha; TNFR1: Tumour necrosis factor receptor 1; TRADD: TNFR1-associated death domain protein; TRAF2: TNF receptor associated factor 2.

Detecting necroptosis in retinal cells

Therapeutic options that target necroptosis in the retina
Newly identified chemical entities, including selective inhibitors, drugs, and chemical agents, have been found to modulate the necroptotic cascade pathway and may have potential therapeutic applications for various retinal disorders.¹

Figure 2. Domain organisation of necroptotic signalling proteins and their targeted chemical inhibitors¹

Adapted from: Zhang Q, et al. Int J Biol Sci. 2023.
KD: Kinase domain; ID: Intermediate domain; RHIM: RIP homotypic interaction motif domain; NED: N-terminal execution domain; psKD: C-terminal pseudokinase domain; RIPK1: Activated receptor-interacting protein 1; RIPK3: Activated receptor interacting protein 1; MLKL: Mixed-lineage kinase domain-like pseudokinase.