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). 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. 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. 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. 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. 

/pdf/regulated-cell-death-rcd-in-cancer-key-pathways-and-targeted-1zhjnd92.pdf

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Preparation and application of pH-responsive drug delivery systems.

Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.

Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.

Enzymes are a class of natural catalysts with high efficiency, specificity, and selectivity unmatched by their synthetic counterparts and dictate a myriad of reactions that constitute various cascades in living cells. The development of suitable supports is significant for the immobilization of structurally flexible enzymes, enabling biomimetic transformation in the extracellular environment. Accordingly, porous organic frameworks, including metal organic frameworks (MOFs), covalent organic frameworks (COFs) and hydrogen-bonded organic frameworks (HOFs), have emerged as ideal supports for the immobilization of enzymes because of their structural features including ultrahigh surface area, tailorable porosity, and versatile framework compositions. Specially, organic framework-encased enzymes have shown significant enhancement in stability and reusability, and their tailorable pore opening provides a gatekeeper-like effect for guest sieving, which is beneficial for mimicking intracellular biocatalysis processes. This immobilization technique brings new insight into the development of next-generation enzyme materials and shows huge potential in healthcare applications, such as biomarker diagnosis, biostorage, and cancer and antibacterial therapies. In this review, we describe the state-of-the-art strategies for the structural immobilization of enzymes using the well-explored MOFs and burgeoning COFs and HOFs as scaffolds, with special emphasis on how these porous framework-confined technologies can provide a favorable microenvironment for mimicking natural biocatalysis. Subsequently, advanced characterization techniques for enzyme conformation, the effect of the confined microenvironment on the activity of enzymes, and the emerging healthcare applications will be surveyed.

Confining enzymes in porous organic frameworks: from synthetic strategy and characterization to healthcare applications.

Glutathione peroxidase 4 (GPx4) moonlights as structural protein and antioxidase that powerfully inhibits lipid oxidation. In the past years, it is considered as a key regulator of ferroptosis, which takes role in the lipid and amine acid metabolism and influences the cell aging, oncogenesis, and cell death. More and more evidences show that targeting GPX4-induced ferroptosis is a promising strategy for disease therapy, especially cancer treatment. In view of these, we generalize the function of GPX4 and regulatory mechanism between GPX4 and ferroptosis, discuss its roles in the disease pathology, and focus on the recent advances of disease therapeutic potential. 

GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment.

Smart biomimetic metal organic frameworks based on ROS-ferroptosis-glycolysis regulation for enhanced tumor chemo-immunotherapy

Non-apoptotic cell death such as ferroptosis and pyroptosis has shed new light on cancer treatment, whereas combinational therapy using both these mechanisms has not yet been fully explored. Herein, a dual-inductive nano-system to realize ferroptosis/pyroptosis mediated anti-cancer effects is presented. The nanodrug (Tf-LipoMof@PL) is constructed with a piperlongumine (PL) loaded metal-organic framework (MOF) coated with transferrin decorated pH sensitive lipid layer. Intracellular iron was enriched with an iron-containing MOF, whose endocytosis can be further facilitated by transferrin decorated on the lipid layer, which provides a prerequisite for the occurrence of ferroptosis and pyroptosis. Piperlongumine as the ferroptosis inducer can strengthen the ferroptotic cell death, and provide H2O2 for the dual induction system to increase ROS generation through Fenton reaction. On the basis of validation of both ferroptosis and pyroptosis, the dual-inductive nanodrug demonstrated ideal anticancer effects in the xenograft mice model, which proved that the ferroptosis/pyroptosis dual-inductive nanoplatform could be an effective and promising anticancer modality.

Ferroptosis/pyroptosis dual-inductive combinational anti-cancer therapy achieved by transferrin decorated nanoMOF

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Smart biomimetic metal organic frameworks based on ROS-ferroptosis-glycolysis regulation for enhanced tumor chemo-immunotherapy

Ferroptosis/pyroptosis dual-inductive combinational anti-cancer therapy achieved by transferrin decorated nanoMOF