4. Therapeutic potential of targeting necroptosis in therapies of organ fibrosis
For a long time, fibrosis in multiple organs/tissues seriously affects human physical and mental health. Despite diversified treatment strategies have been attempted to suppress and treat fibrosis, the therapeutic effects still poor (Hu et al. 2020, Han et al. 2021). As a consequence, finding effective therapeutic drugs for treating organ fibrosis is an urgent matter to be solved. In view of the vital function of necroptosis, this review collected the present molecules that aimed at necroptosis and could be considered as promising therapy in treating organ fibrosis. Here, the natural and/or synthetic necroptosis inhibitors for the prevention and treatment of organ fibrosis were highlighted in Table 1. Norberto et al reported that RIPK1 inhibitors Necrostatin-1s, -1, -5, or -7 all can reverse the necroptosis of macrophage. However, Necrostatin-1s, and -1 were demonstrated unsuitable for application in humans due to further drawbacks such as short half-life in vivo and poor metabolic stability (Berger et al. 2015). In addition, RIPK3 inhibitor GSK’872 can completely blocked mouse alveolar macrophages death following Smarcescens  infection (Gonzalez-Juarbe et al. 2015). Dabrafenib is a noted inhibitor of B-Raf, which has been approved for clinical use for melanoma and thyroid cancers expressing B-Raf V600E mutations (Salama et al. 2020). Interestingly, recent studies found that dabrafenib is also a RIPK3 inhibitor, which has been proved in multiple models including human hepatocytes, hepatic injury mice models, and ischemic brain injury (Shi et al. 2020a). Primidone, a FDA-approved aromatic antiepileptic drug was found also an effective inhibitor of RIPK1 in vitro and in a murine model of TNFα-induced shock (Riebeling et al. 2021). So far, new drugs targeting key proteins of necroptosis are mainly inhibitors, and agonists haven’t been found yet. In total, the above studies have shown that inhibiting necroptosis has broad development prospects for the treatment of various diseases including organ fibrosis. Given that necroptosis pathway is an effective target for treating organ fibrosis, RIPK1/3 or MLKL inhibitors are expected to be a candidate drug for ameliorate fibrosis and should be further explored.