Tissue and Cell, Год журнала: 2024, Номер 87, С. 102323 - 102323
Опубликована: Фев. 4, 2024
Язык: Английский
Redox Biology, Год журнала: 2023, Номер 63, С. 102754 - 102754
Опубликована: Май 18, 2023
Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one the most significant biological events cancer progression. Cancer cells generally represent a higher level, which suggests dual therapeutic strategy by regulating status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, exhibits great anti-cancer capability, attributing to accumulation within cells, whereas restore homeostasis has been claimed fail several clinical practices. Targeting vulnerability pro-oxidants capable generating excessive reactive oxygen species (ROS) surfaced an important strategy. However, multiple adverse effects caused indiscriminate attacks uncontrolled drug-induced OS on normal tissues and drug-tolerant capacity some certain greatly limit their further applications. Herein, we review representative oxidative drugs summarize side organs, emphasizing that seeking balance between damage value exploiting next-generation OS-based chemotherapeutics.
Язык: Английский
Процитировано
105
Cell Metabolism, Год журнала: 2023, Номер 35(8), С. 1283 - 1303
Опубликована: Авг. 1, 2023
Язык: Английский
Процитировано
101
Nature Cancer, Год журнала: 2024, Номер 5(3), С. 384 - 399
Опубликована: Март 22, 2024
Язык: Английский
Процитировано
66
Molecular Cell, Год журнала: 2023, Номер 84(1), С. 23 - 33
Опубликована: Ноя. 28, 2023
Язык: Английский
Процитировано
54
Antioxidants, Год журнала: 2024, Номер 13(1), С. 70 - 70
Опубликована: Янв. 2, 2024
Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related 2 (NRF2) a critical transcription that regulates the antioxidant systems response oxidative stress by governing expression genes encoding enzymes shield cells from diverse alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been focus numerous investigations elucidating whether suppresses tumor promotion or conversely exerts pro-oncogenic effects. has found participate pathological including dysregulated cell proliferation, metabolic remodeling, resistance apoptosis. Herein, this review article will examine intriguing role phase separation activating transcriptional activity explore dual impacts on immunology, cancer stem cells, metastasis, long non-coding RNAs (LncRNAs). Taken together, aims discuss multifaceted both prevention while also addressing advantages, disadvantages, limitations associated with modulating therapeutically treatment.
Язык: Английский
Процитировано
30
Cell, Год журнала: 2024, Номер 187(10), С. 2536 - 2556.e30
Опубликована: Апрель 22, 2024
Язык: Английский
Процитировано
25
Cell Metabolism, Год журнала: 2024, Номер 36(7), С. 1504 - 1520.e9
Опубликована: Июнь 13, 2024
Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various disorders cancer electron transport chain (ETC) blockade. These analyses revealed extensive perturbations purine metabolism, stable isotope tracing demonstrated that ETC defects suppress de novo synthesis while enhancing salvage. In lung cancer, tumors markers of low oxidative metabolism exhibit enhanced expression the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) high levels HPRT1 product inosine monophosphate. Mechanistically, blockade activates pentose phosphate pathway, providing diphosphate drive supplied by uptake extracellular bases. Blocking sensitizes inhibition. findings demonstrate remodel upon uncover a new vulnerability respiration.
Язык: Английский
Процитировано
22
Nature, Год журнала: 2025, Номер unknown
Опубликована: Фев. 12, 2025
Abstract UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, substrate receptor the CUL3–RING E3 ubiquitin ligase (CRL3) complex, promotes degradation LSD1–CoREST corepressor thereby limiting attrition 2,3 However, direct target and mechanism action remain unclear. Here we show that acts as molecular glue to induce high-affinity interactions between KBTBD4 HDAC1/2 promote degradation. Through proteomics chemical inhibitor studies, identify principal HDAC1/2. Cryo-electron microscopy analysis dimeric bound LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which single molecule enables pair KELCH-repeat propeller domains recruit HDAC1 catalytic domain. One partially masks rim active site, exploited by extend E3–neosubstrate interface. The other cooperatively strengthens binding through distinct overall CoREST–HDAC1/2–KBTBD4 interaction further buttressed endogenous cofactor inositol hexakisphosphate, second glue. functional relevance quaternary surfaces demonstrated base editor scanning delineating its action, reveal how cooperativity offered CRL3 can be leveraged small degrader.
Язык: Английский
Процитировано
8
Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)
Опубликована: Март 7, 2025
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.
Язык: Английский
Процитировано
5
Nature Metabolism, Год журнала: 2025, Номер unknown
Опубликована: Фев. 6, 2025
Язык: Английский
Процитировано
3