1. Introduction
Fibrotic diseases with high morbidity and mortality all over the world (Klinkhammer, Floege and Boor 2018, Henderson, Rieder and Wynn 2020) are characterized by excessive deposition of extracellular matrix (ECM) (Distler et al. 2019). It can potentially affect all organs and tissues in the body including multisystem diseases such as systemic sclerosis as well as individual organs containing pulmonary, kidney, hepatic, cardiac and bladder fibrosis(shown in Fig 1) (Rosenbloom, Ren and Macarak 2016). At present, there are few effective drugs for the direct treatment of fibrosis in clinic. A large number of diseases related to fibrosis urgently need specific drugs to improve the survival status of patients.
Fibrosis is the common outcome of tissue repair response which tends to be dysregulated following kinds of trigger and tissue injury, most significantly during chronic inflammatory diseases (Henderson et al. 2020). The excessive accumulation of ECM components including collagen and fibronectin, is a common and significant stage of tissue repair process in all organs. When tissues are damaged, local tissue fibroblasts tend to activate and occurred a series of changes including enhance their contractility, secrete inflammatory mediators, and excessive generated of ECM components, which sponsor the wound-healing response. When the injury reduced or vanished, the wound-healing response tend to be effective, exhibiting in only a short-lived enhance of the accumulation of ECM components and promoting the renewal of functional tissue structure. In contrast, when the injury persistent existence, the wound-healing response transformed into microenvironmental changes including ECM generating cells raise in amount or become immoderately active, which eventually leads to the formation of substantial scar formation and injury of normal organ structure (Pakshir and Hinz 2018).
In the different organs, a good deal of clinical research and animal experiments’ evidence has obviously built the strong connection of cell death with fibrosis (Weiskirchen, Weiskirchen and Tacke 2019). Over the last decade, it has become definite that there are many forms of cell death, and diverse forms of cell death can be triggered in diseases, initiating different replies and biological results (Sauler, Bazan and Lee 2019). Regulated cell death (RCD) is a primary approach for human body to cleanup injured, infected, or surplus cells. In the past, apoptosis was considered the unique form of RCD. However, recent studies have discovered several new modes of RCD including necroptosis, pyrolysis, ferroptosis and autophagic cell death (Stockwell et al. 2017, Vande Walle and Lamkanfi 2016, Choi et al. 2019, Tang et al. 2020). With the in-depth understanding of the RCD mechanism, more and more evidence indicated that these RCD mechanisms are closely related to organ fibrosis (Shojaie, Iorga and Dara 2020, Schwabe and Luedde 2018). By straightly obstructing the mediators that regulate each mode of RCD or promote the mediators that response to certain types of RCD may bring us new opportunities to treat fibrotic diseases. The latest research shows that apoptosis and necroptosis emerge higher research value in the process of fibrosis, compared with pyrolysis, ferroptosis and autophagy(Schwabe and Luedde 2018). In addition, compared with apoptosis, necroptosis can cause cellular contents to flow out, further trigger a large amount of inflammation, accelerate the process of fibrosis, and may lead to the irreversibility of fibrosis. Therefore, the aim of this review is to summarize our understanding of the necroptosis in organ fibrosis, so as to provide certain research ideas for the therapy of organ fibrosis or the development of new drugs.