Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half‐life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)‐sensitive polymer (PHPM) is designed, which is used to co‐encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA‐Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti‐programmed cell death protein ligand‐1 antibody (αPD‐L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD‐L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Deadly actin collapse by disulfidptosis

4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer.

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decay in cellular functions and proliferation, resulting in increased cellular damage and death. This condition plays an essential role in the aging process and significantly contributes to the development of age-related complications. On the other hand, ferroptosis is a systemic cell death pathway characterized by excessive iron accumulation followed by the generation of reactive oxygen species (ROS). Oxidative stress is a common trigger of this condition and may be induced by various factors such as toxins, drugs, and inflammation. Ferroptosis is linked to numerous disorders, including cardiovascular disease, neurodegeneration, and cancer. Senescence is believed to contribute to the decay in tissue and organ functions occurring with aging. It has also been linked to the development of age-related pathologies, such as cardiovascular diseases, diabetes, and cancer. In particular, senescent cells have been shown to produce inflammatory cytokines and other pro-inflammatory molecules that can contribute to these conditions. In turn, ferroptosis has been linked to the development of various health disorders, including neurodegeneration, cardiovascular disease, and cancer. Ferroptosis is known to play a role in the development of these pathologies by promoting the death of damaged or diseased cells and contributing to the inflammation often associated. Both senescence and ferroptosis are complex pathways that are still not fully understood. Further research is needed to thoroughly investigate the role of these processes in aging and disease, and to identify potential interventions to target such processes in order to prevent or treat age-related conditions. This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, ferroptosis, aging, and disease, and whether they can be exploited to block or limit the decay of the physiological functions in elderly people for a healthy longevity.

Ferroptosis and Senescence: A Systematic Review

Phase-separated membraneless organelles often contain RNAs that exhibit unusual semi-extractability upon the conventional RNA extraction method, and can be efficiently retrieved by needle shearing or heating during RNA extraction. Semi-extractable RNAs are promising resources for understanding RNA-centric phase separation. However, limited assessments have been performed to systematically identify and characterize semi-extractable RNAs. In this study, 1,074 semi-extractable RNAs were identified across five human cell lines, including ASAP1, DANT2, EXT1, FTX, IGF1R, LIMS1, NEAT1, PHF21A, PVT1, SCMH1, STRG.3024.1, TBL1X, TCF7L2, TVP23C-CDRT4, UBE2E2, ZCCHC7, ZFAND3, and ZSWIM6, which exhibited consistent semi-extractability. By integrating publicly available datasets, we found that semi-extractable RNAs tend to be distributed in the nuclear compartments but are dissociated from the chromatin. Long and repeat-containing semi-extractable RNAs act as hubs to provide global RNA-RNA interactions. Semi-extractable RNAs were divided into four groups based on their k-mer content. The NEAT1 group preferred to interact with paraspeckle proteins, such as FUS and NONO, implying that RNAs in this group are potential candidates of architectural RNAs that constitute nuclear bodies.

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Landscape of semi-extractable RNAs across five human cell lines

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments. 

/pdf/targeting-cell-death-pathways-for-cancer-therapy-recent-1s2ymajs.pdf

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Liquid-liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis. 

/pdf/liquid-liquid-phase-separation-in-tumor-biology-1xw1y8cb.pdf

Liquid–liquid phase separation in tumor biology

Rainfall is one of the core components of the water cycle in terrestrial ecosystems and is closely related to hydrothermal balance, plant and animal growth, and stability of the whole ecosystem. Long-duration rainstorms can alter the soil structure of forest ecosystems and affect the spatial distribution of soil moisture, thus affecting the water supply from the soil to trees and being one of the factors that increase the vulnerability of forest ecosystems. In recent years, changes in rainfall patterns have normalized prolonged heavy rainfall in the mountainous areas of North China. However, there are few reports on the response of soil water at different depths to historically long rainstorms in forested areas. By quantifying the relationship between precipitation characteristics and soil water, the soil water transport patterns of Platycladus orientalis (PO), Quercus variabilis (QV) and Pinus tabuliformis (PT) during the long-duration rainstorms of 21–22 July 2012 were evaluated separately, and the roles of different plants in response to the historically long rainstorm were determined. The results showed that (1) the response of different forest stands to rainfall had a lag. Among them, the soil water of PO and PT were less affected by rainfall and could maintain a relatively stable state. (2) The soil moisture transport trend of PO was significantly greater than that of other vegetation zones and covered the whole process of rainfall. Under the three typical vegetation covers, there was a continuous zero-flux plane in the soil at each observed depth (the direction of soil moisture flow is more stable over the rainfall period), but there was no regular transport trend. (3) The root system was an important factor, influencing the differences in soil moisture response of the three vegetation types. QV had a higher average effective water recharge rate than lateral cypress and oleander and could better utilize the water recharge from storm water.

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Xuhui Tong

Papers

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Liquid–liquid phase separation in tumor biology

Response of Soil Moisture to Long-Duration Rainstorms in Three Forest Stands in Mountainous Areas of North China