5. Open questions, translation and future directions
The research history of necroptosis pathway has last decades of years from the term of necroptosis first created to express this nonapoptotic RCD form at 2005. Up to now, RIPK1/3 and MLKL as the main proteins of necroptosis have reached an agreement in necroptosis research field. However, the specific upstream/downstream protein targets of necroptosis have not been fully elucidated. Therefore, the pathophysiology effect of necroptosis in diseases was still unclear and even remains controversial. For example, acetaminophen poisoning is the most correlative factor for drug-induced liver injury (DILI) in the clinic (Krenkel, Mossanen and Tacke 2014). Several studies came to different and controversial conclusions on the effect of necroptosis in DILI, probably due to this pathway was modulated by different technical methods, including small molecule protein inhibitor Nec-1, anti-sense oligonucleotides against RIPK1/3 mRNA, or conditional knockout of RIP kinases(Takemoto et al. 2014, Dara et al. 2015, Li et al. 2014, Ramachandran et al. 2013). Though the physiological effect of necroptosis has many pending issues, the current plenty studies have already showing its broad outlook on organ fibrosis and even other dieases. Given that necroptosis is a method for treating organ fibrosis, RIPK1/3 and MLKL inhibitors are expected to be a candidate drug for improving organ fibrosis and should be further explored.
Acknowlegment
This work has been financially supported by the National Natural Science Foundation of China (82003948), Zhejiang Province Basic Public Welfare Research Project (LQ21H280002), Basic Public Welfare Research Project in Zhejiang province (LGF18H280003), Zhejiang Traditional Chinese Medicine Science and Technology Plan (2021ZB084), Zhejiang Chinese Medicine University School-level Scientific Research Fund for Talents (2020ZR14).