2.4 Necroptosis related signaling pathway
The different kinds of RCD can be regard as an individual, concerted cell death system, in which the single pathways are closely interrelated and mutual coordinate for each other. These interaction describes a complicated molecular signal network can be consider as a homeostatic mechanism for the organism (Galluzzi et al. 2017) (show in Fig 4). Therefore, it is not difficult to understand that necroptosis signal pathway is closely related with several other forms of RCD containing apoptosis, autophagy and ferroptosis. It has mentioned above, casepase 8 is seems like a key switch between apoptosis and necroptosis, due to its cleaving capacity of RIPK1 and RIPK3. In addition, apoptosis and necroptosis share the upstream TNFR pathway, mainly including FADD, cellular FLICE-inhibitory protein (cFLIP), caspase 8, cylindroma protein (CYLD) and various inhibitor of apoptosis protein (IAP) family members that interact with TNFR1(Oberst et al. 2011, Dillon et al. 2012). Moreover, caspase 6 is the downstream regulator of apoptosis and cathepsins can leading to lysosomal injury by accelerates permeation of mitochondrial outer membrane (Galluzzi, Bravo-San Pedro and Kroemer 2014). Both caspase 6 and cathepsins can proteolytic inactivate RIPK1 to exert necroptosis-inhibitory effects (van Raam et al. 2013, McComb et al. 2014b). Researches have shown that, in transformed cells, autophagy can promote necroptosis by ROS accumulation (Chen et al. 2011). In addition, autophagy-related protein 16-1 can interdicts necroptosis in the intestinal epithelium (Matsuzawa-Ishimoto et al. 2017). Moreover, it is reported that glutathione peroxidase 4, the primary endogenous inhibitor of ferroptosis, can mediates powerful necroptosis inhibition effects in erythroid precursor cells (Canli et al. 2016). Besides different forms of RCD mentioned above, necroptosis also intimately connected with inflammation, oxidative stress and many other physiopathological processes (Galluzzi et al. 2017). Ca(2+)-calmodulin-dependent protein kinase is a RIPK3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis (Zhang et al. 2016b). Recent literature indicated that necroptosis is a primary mechanism of retinal pigment epithelial (RPE) cell death in response to oxidative stress (Hanus, Anderson and Wang 2015). It is well known that reactive oxygen species (ROS) can be regarded as a driving force of necroptosis. ROS can trigger RIPK1 autophosphorylation on S161 by modify three crucial cysteine residues which is necessary for RIP3 recruitment into necrosome complex of necroptosis (Zhang et al. 2017). In addition, studies show that TNFα-mediated necroptosis accelerates increased transcription of inflammatory cytokine gene by a cell-autonomous mechanism involving NF-κB and p38 (Zhu et al. 2018a). In a word, it has been demonstrated that necroptosis participate in cell death in diverse disease conditions, including organ fibrosis, viral infection, acute kidney injury, and cardiac I/R (Galluzzi et al. 2017, Schwabe and Luedde 2018). In this review, we aim to focus on the relationship between the pathological process of necroptosis and tissue fibrosis, as well as potential drug targets of necroptosis for the clinical treatment of fibrotic diseases.