Preface

Cell death plays an important role in various physiological and pathological conditions. It is a process involving the growth and differentiation of cells, death of normal cells, and cleaning of abnormal cells. The dysregulation of the cell death process may lead to diverse diseases.

There are two main types of cell death: necrosis and programmed cell death (PCD). Necrosis is an unregulated, passive process characterized by organelle and cell membrane destruction. PCD is an active extinction process, including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Among them, the most studied PCD processes are apoptosis, autophagy, and ferroptosis. Apoptosis is an orderly cell death. There are two types of apoptosis: exogenous apoptosis via death receptor pathway, and endogenous apoptosis via mitochondrial pathway. Autophagy is a self-eating process. It serves to degrade impaired organelles and malformed proteins via autophagosomes and recycle and reuse them for cell functions. Ferroptosis is a recently discovered PCD. It is a process of iron-dependent lipid peroxidation. It usually causes a dense mitochondrial membrane and the loss of glutathione peroxidase 4.

In Section 1, "Cell Death", Chapter 1 summarizes the role of epigenetic regulation of cell death in cancer. For example, the role of epigenetic regulations in apoptosis including the DNA hypermethylation on FAS receptor, BCL-2, and Apaf-1; their role in DNA hypomethylation on chromosomal stability; and their role in the histone methylation on BIM. It also discusses the role of epigenetic regulations in other forms of cell death, including necroptosis, pyroptosis, ferroptosis, NETosis, immunogenic cell death, and parthanatos. In Chapter 2, proline-rich peptide (PRP-1) is isolated from neurosecretory granules of the bovine neurohypophysis. PRP-1 has been shown to have the opposite effects on cell death in neurodegenerative diseases and cancer. It significantly reduces staurosporine-induced apoptosis of postnatal hippocampal cells, as well as doxorubicin-induced apoptosis of bone marrow monocytes and granulocytes. PRP-1 also exerts the opposite effect on the proliferation of bone marrow stromal cells obtained from normal humans and on the stromal cells isolated from the human giant-cell tumor. PRP-1 cytostatically inhibits chondrosarcoma bulk tumors but exerts a drastic cytotoxic effect on sarcomas cancer stem cells.

In Section 2, "Ferroptosis", Chapter 3 discusses the role of ferroptosis in tumorigenesis, progression, and chemoresistance of different types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML), and chronic lymphocytic leukemia (CLL). Furthermore, both activators and inhibitors of ferroptosis have been identified and used to study the molecular mechanisms underlying ferroptosis, thus paving the way toward designing new therapeutic strategies for treating ferroptosis-related diseases. In Chapter 4, ferroptosis is reported to be responsible for several neurological disorders; however, the underlying mechanism is not fully elucidated. This chapter reviews the role of ferroptosis in neurological disorders. For example, the ferroptosis-related gene, the

ferroptosis regulators, and their role in ferroptosis-related neurological diseases. Chapter 5 discusses the role of iron and ferroptosis in chronic diseases, including (1) its role in tumors, such as in hepatocellular carcinoma, pancreatic cancer, renal cell carcinoma, breast cancer, bladder tumor, and tumor-associated ferroptosis regulatory protein (SLC7A11, p53, NRF2, ACSL4, GPX4, FSP1); (2) its role in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and (3) its role in cardiovascular and cerebrovascular disease.

In Section 3, "Autophagy", Chapter 6 presents the authors' study demonstrating that overactivation of the mTOR pathway in the liver promotes de novo lipid synthesis and eventually the formation of non-inflammatory hepatocellular carcinoma (HCC). The mechanism study reveals that persistent activation of the mTOR pathway promotes the de novo synthesis of lipids, resulting in the production of a large amount of lipid in the liver; meanwhile, it also inhibits autophagy, resulting in the inability of lipids to be removed in time and its accumulation in the liver. Accumulated lipid peroxidation is responsible for the development of HCC. In addition, the persistently activated mTOR pathway inhibits the release of exosomes. The reduced release of exosomes may impair intercellular communication, especially with immune cells, thereby making HCC more prone to invasion and metastasis with less inflammation.

Despite significant achievements in the study of cell death and its role in diverse diseases in recent years, the mechanisms underlying cell death are still not fully elucidated. It is believed that based on a further understanding of the role and mechanism of cell death in diseases, more patients will benefit from novel treatment strategies targeting cell death. This book is a useful resource in this regard.

> **Ke Xu** Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
