Necroptosis: A Pathogenic Negotiator in Human Diseases

Abstract

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson’s Disease

“…Necroptosis is closely related to many diseases, including inflammatory diseases and neurodegenerative diseases. 44,45 The results observed in our experiments indicate that LZWL02003 may play a role by interfering with the necroptosis pathway, which needs further confirmation, and relevant research is currently in progress.…”

“…Nec-1 is a highly specific and effective necrotic apoptosis inhibitor that can penetrate the blood–brain barrier, and it is also an allosteric inhibitor of ATP competitive receptor-interacting protein kinase 1 (RIPK1). , It is a crucial upstream kinase involved in the activation of necroptosis. Necroptosis is closely related to many diseases, including inflammatory diseases and neurodegenerative diseases. , The results observed in our experiments indicate that LZWL 02003 may play a role by interfering with the necroptosis pathway, which needs further confirmation, and relevant research is currently in progress.…”

PROTACs Targeting MLKL Protect Cells from Necroptosis

“…The crude residue was purified by silica gel column chromatography (10−60% ethyl acetate:cyclohexane) to yield the title compound as a brown oil (185 mg, 0.60 mmol, 70%). UHPLC R t = 5.95 min (conditions A: 0 to 100 vol.% B over 10 min, λ = 254 nm); 1 H NMR (300 MHz, CDCl 3 ) δ 7.03 (tt, J = 7.9, 0.9 Hz, 1H), 6 (2 mL), and the reaction mixture was heated at 70 °C for 1 h. The reaction was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with sat.…”

“…1 While the necroptosis pathway has only been recently described, it has garnered significant interest as a potential therapeutic target for a broad range of pathologies including oncogenic, 2 neurodegenerative, 3 hepatic, 4 autoimmune, 5 and inflammatory conditions. 6 Necroptosis can be initiated by a number of disparate stimuli including cytokines such as TNF-α (TNFR1), 7 double-stranded RNA and lipopolysaccharides (TLR3/4), 8 and IFN-γ signaling (IFNAR1). 9 While these pathways vary in the upstream signaling cascades, they all converge to the activation of Receptor Interacting Protein Kinase 3 (RIPK3) and MLKL (Figure 1).…”

“…Necroptosis is a proinflammatory, regulated form of cell death characterized by rupture of the cell membrane and release of Damage Associated Molecular Patterns (DAMPs) . While the necroptosis pathway has only been recently described, it has garnered significant interest as a potential therapeutic target for a broad range of pathologies including oncogenic, neurodegenerative, hepatic, autoimmune, and inflammatory conditions . Necroptosis can be initiated by a number of disparate stimuli including cytokines such as TNF-α (TNFR1), double-stranded RNA and lipopolysaccharides (TLR3/4), and IFN-γ signaling (IFNAR1) .…”