Ferroptosis is a novel characterized form of cell death featured with iron-dependent lipid peroxidation, which is distinct from any known programmed cell death in the biological processes and morphological characteristics. Recent evidence points out that ferroptosis is correlated with numerous metabolic pathways, including iron homeostasis, lipid metabolism, and redox homeostasis, associating with the occurrence and treatment of hematological malignancies, such as multiple myeloma, leukemia, and lymphoma. Nowadays, utilizing ferroptosis as the target to prevent and treat hematological malignancies has become an active and challenging topic of research, and the regulatory network and physiological function of ferroptosis also need to be further elucidated. This review will summarize the recent progress in the molecular regulation of ferroptosis and the physiological roles and therapeutic potential of ferroptosis as the target in hematological malignancies.

Ferroptosis is a novel characterized form of cell death featured with iron-dependent lipid peroxidation, which is distinct from any known programmed cell death in the biological processes and morphological characteristics. Recent evidence points out that ferroptosis is correlated with numerous metabolic pathways, including iron homeostasis, lipid metabolism, and redox homeostasis, associating with the occurrence and treatment of hematological malignancies, such as multiple myeloma, leukemia, and lymphoma. Nowadays, utilizing ferroptosis as the target to prevent and treat hematological malignancies has become an active and challenging topic of research, and the regulatory network and physiological function of ferroptosis also need to be further elucidated. This review will summarize the recent progress in the molecular regulation of ferroptosis and the physiological roles and therapeutic potential of ferroptosis as the target in hematological malignancies.

p97, also known as valosin-containing proteinor CDC48, is a member of the AAA protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget's disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small-molecule inhibitors have been deployed against p97, including his (diethyldithiocarbamate')copper and CB-5083, which entered the first phase of clinical tests hut failed. One bottleneck in the design of p97 drugs is that its molecular mechanism remains unclear. This paper summarizes recent studies on the molecular mechanisms of p97, which may lead to insight into how the next generation of small molecules targeting p97 can he designed.

Protein ubiquitination regulates almost every process in eukaryotic cells. The study of the many enzymes involved in the ubiquitination system and the development of ubiquitination-associated therapeutics are important areas of current research. Synthetic tools such as ubiquitin-based chemical probes have been making an increasing contribution to deciphering various biochemical components involved in ubiquitin conjugation, recruitment, signaling, and deconjugation. In the present minireview, we summarize the progress of ubiquitin-based chemical probes with an emphasis on their various structures and chemical synthesis. We discuss the utility of the ubiquitin-based chemical probes for discovering and profiling ubiquitin-dependent signaling systems, as well as the monitoring and visualization of ubiquitin-related enzymatic machinery. We also show how the probes can serve to elucidate the molecular mechanism of recognition and catalysis. Collectively, the development and application of ubiquitin-based chemical probes emphasizes the importance and utility of chemical protein synthesis in modern chemical biology.

p97, also known as valosin-containing proteinor CDC48, is a member of the AAA protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget's disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small-molecule inhibitors have been deployed against p97, including his (diethyldithiocarbamate')copper and CB-5083, which entered the first phase of clinical tests hut failed. One bottleneck in the design of p97 drugs is that its molecular mechanism remains unclear. This paper summarizes recent studies on the molecular mechanisms of p97, which may lead to insight into how the next generation of small molecules targeting p97 can he designed.

Ubiquitination is one of the most extensive post-translational modifications in eukaryotes and is involved in various physiological processes such as protein degradation, autophagy, protein interaction, and protein localization. The ubiquitin (Ub)-related protein machines include Ub-activating enzymes (E1s), Ub-conjugating enzymes (E2s), Ub ligases (E3s), deubiquitinating enzymes (DUBs), p97, and the proteasomes. In recent years, the role of DUBs has been extensively studied and relatively well understood. On the other hand, the functional mechanisms of the other more complex ubiquitin-processing protein machines (e.g., E3, p97, and proteasomes) are still to be sufficiently well explored due to their intricate nature. One of the hurdles facing the studies of these complex protein machines is the challenge of developing tailor-designed structurally defined model substrates, which unfortunately cannot be directly obtained using recombinant technology. Consequently, the acquisition and synthesis of the ubiquitin tool molecules are essential for the elucidation of the functions and structures of the complex ubiquitin-processing protein machines. This paper aims to highlight recent studies on these protein machines based on the synthetic ubiquitin tool molecules.

Disulfide bond-containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid-phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA-based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA-based disulfide surrogates are described.

Ubiquitination is one of the most extensive post-translational modifications in eukaryotes and is involved in various physiological processes such as protein degradation, autophagy, protein interaction, and protein localization. The ubiquitin (Ub)-related protein machines include Ub-activating enzymes (E1s), Ub-conjugating enzymes (E2s), Ub ligases (E3s), deubiquitinating enzymes (DUBs), p97, and the proteasomes. In recent years, the role of DUBs has been extensively studied and relatively well understood. On the other hand, the functional mechanisms of the other more complex ubiquitin-processing protein machines (e.g., E3, p97, and proteasomes) are still to be sufficiently well explored due to their intricate nature. One of the hurdles facing the studies of these complex protein machines is the challenge of developing tailor-designed structurally defined model substrates, which unfortunately cannot be directly obtained using recombinant technology. Consequently, the acquisition and synthesis of the ubiquitin tool molecules are essential for the elucidation of the functions and structures of the complex ubiquitin-processing protein machines. This paper aims to highlight recent studies on these protein machines based on the synthetic ubiquitin tool molecules.

Native chemical ligation (NCL) has become one of the most important methods in chemical syntheses of proteins. Recently, in order to expand its scope, considerable effort has been devoted to tuning the C-terminal acyl donor thioesters used in NCL. This article reviews the recent advances in the design of C-terminal acyl donors, their precursors and surrogates, and highlights some noteworthy progress that may lead the future direction of protein chemical synthesis.