2 Cancer is a heterogeneous disease characterized by cell death disorder.
For example, the epidermal growth factor receptor (EGFR) mutation rate of lung adenocarcinoma patients in China is 61%, while that in the United States is only 11%. Cancer has become one of the most common diseases in China, 1 which also has unique epidemiological characteristics and patient types. The biennial report 2020–2021 issued by the international agency for research on cancer (IARC) of the World Health Organization points out that the reality of high incidence of cancer and the rising trend also make cancer one of the main reasons that threaten human life. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD).
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