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).