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 S . marcescens 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.