Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy DOI

Zifeng Tang,

Jie Li,

Lijie Peng

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(3), P. 1872 - 1887

Published: Jan. 24, 2024

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is broad interest in development GPX4 inhibitors. However, majority reported inhibitors utilize chloroacetamide reactive electrophilic warhead, and selectivity pharmacokinetic properties still need to be improved. Herein, we developed compound library based on novel sulfonyl ynamide, executed phenotypic screening against pancreatic cell lines. Notably, one A16 exhibiting potent toxicity was identified. Further chemical proteomics investigations have demonstrated that specifically targets under both situ vivo conditions, inducing Importantly, exhibited superior potency compared inhibitors, ML210 ML162. This provides structural diversity tool probes unraveling fundamental biology exploring therapeutic potential via ferroptosis induction.

Language: Английский

Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies DOI Creative Commons
Qian Zhou,

Yu Meng,

Daishi Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

Citations

153
The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions DOI Open Access
Guang Lei, Li Zhuang, Boyi Gan

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(4), P. 513 - 534

Published: April 1, 2024

Language: Английский

Citations

116
A guideline on the molecular ecosystem regulating ferroptosis DOI
Enyong Dai, Xin Chen, Andreas Linkermann

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(9), P. 1447 - 1457

Published: Feb. 29, 2024

Language: Английский

Citations

74
Ferroptosis: principles and significance in health and disease DOI Creative Commons
Fangquan Chen, Rui Kang, Daolin Tang

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 6, 2024

Abstract Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic pathway in 2012, ferroptosis has emerged crucial mechanism numerous physiological pathological contexts, leading to significant therapeutic advancements across wide range diseases. This review summarizes the fundamental mechanisms regulatory pathways underlying ferroptosis, including both GPX4-dependent -independent antioxidant mechanisms. Additionally, we examine involvement various conditions, cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, metabolic disorders. Specifically, explore role response chemotherapy, radiotherapy, immunotherapy, nanotherapy, targeted therapy. Furthermore, discuss pharmacological strategies for modulating potential biomarkers monitoring this process. Lastly, elucidate interplay between other forms regulated death. Such insights hold promise advancing our understanding context human health disease.

Language: Английский

Citations

51
H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer DOI
Zhang Cai, Lijie Zhou,

Mingyuan Zhang

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(21), P. 3589 - 3601

Published: Aug. 13, 2024

Abstract Recently discovered epigenetic modification lysine lactylation contributes to tumor development and progression in several types of cancer. In addition the tumor-intrinsic effects, histone may mediate microenvironment remodeling immune evasion. this study, we observed elevated pan–lysine H3 18 (H3K18la) levels non–small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption glycolysis by 2-deoxy-D-glucose oxamate treatment silencing lactate dehydrogenase A B reduced H3K18la circumvented evasion NSCLC cells enhancing CD8+ T-cell cytotoxicity. Mechanistically, directly activated transcription pore membrane protein 121 (POM121), enhanced MYC nuclear transport direct binding CD274 promoter induce PD-L1 expression. a mouse xenograft model, combination therapy inhibitor an anti-PD-1 antibody induced intratumoral function exhibited strong antitumor efficacy. Overall, work revealed that potentiates escape activating POM121/MYC/PD-L1 pathway, offers insights into role posttranslational modifications carcinogenesis provides rationale for developing epigenetic-targeted strategy treating NSCLC. Significance: H3K18 supports immunosuppression non-small inducing POM121 increase activity expression, can be reversed metabolic reprogramming immunotherapy treatment.

Language: Английский

Citations

32
Ferroptotic therapy in cancer: benefits, side effects, and risks DOI Creative Commons
Jiandong Diao,

Yuanyuan Jia,

Enyong Dai

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 3, 2024

Abstract Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture intracellular content release. Originally investigated as targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential complement chemotherapy, immunotherapy, radiotherapy in various types. However, it can lead side effects, including immune death, bone marrow impairment, liver kidney damage, cachexia (severe weight loss muscle wasting), secondary tumorigenesis. In this review, we discuss the advantages offer an overview diverse range documented effects. Furthermore, examine underlying mechanisms explore strategies effect mitigation.

Language: Английский

Citations

28
Exploiting ferroptosis vulnerabilities in cancer DOI
Toshitaka Nakamura, Marcus Conrad

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(9), P. 1407 - 1419

Published: June 10, 2024

Language: Английский

Citations

27
“Three birds with one stone” nanoplatform: Efficient near‐infrared‐triggered type‑I AIE photosensitizer for mitochondria‐targeted photodynamic therapy against hypoxic tumors DOI Creative Commons
Sheng-Nan Liu, Yutao Pei, Yan Sun

et al.

Aggregate, Journal Year: 2024, Volume and Issue: unknown

Published: March 24, 2024

Abstract Currently three major problems seriously limit the practical application of cancer photodynamic therapy (PDT): (i) hypoxic tumor microenvironment (TME); (ii) low generation efficiency toxic reactive oxygen species (ROS) in aggregates and (iii) shallow tissue penetration depth excitation light. Very limited approaches are available for addressing all above with a single design. Herein, rational “three birds one stone” molecular nanoengineering strategy is demonstrated: nanoplatform U‐Ir@PAA‐ABS based on covalent combination lanthanide‐doped upconversion nanoparticles (UCNPs) an AIE‐active dinuclear Ir(III) complex provides concentration‐dependent type‐I photochemical process upon 980 nm irradiation by Föster resonance energy transfer (FRET). targets mitochondria has excellent phototoxicity even severe hypoxia environments irradiation, inducing dual‐mode cell death mechanism apoptosis ferroptosis. Taken together, vitro vivo results demonstrate successful improving efficacy PDT against tumors.

Language: Английский

Citations

25
Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader DOI Creative Commons
Xinglin Hu, Xingwei Huang, Yue Yang

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 5529 - 5548

Published: March 21, 2024

Abstract The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact influence each other, specific element that regulates network remains unclear. Dux, a factor known to promote totipotency during from embryonic (ESC) 2C-like ESC (2CLC), has not been extensively studied in context iPSC reprogramming. In this study, we demonstrate modification H3K18la by Dux overexpression controls metabolism-H3K18la-MET network, enhancing efficiency through switch recruitment p300 via its C-terminal domain. Furthermore, our proteomic analysis immunoprecipitation experiment uncovers Brg1 with both being enriched on promoters genes associated pluripotency epithelial junction. summary, study demonstrated significant role Dux-induced early process, highlighting function as potent trigger. Additionally, research revealed, for first time, binding H3K18la, indicating reader histone lactylation.

Language: Английский

Citations

20
Lactylation of HDAC1 Confers Resistance to Ferroptosis in Colorectal Cancer DOI Creative Commons
Zhou Yang, Wei Su, Qinglin Zhang

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti-ferroptosis therapy. Through drug screening, it found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC ferroptosis. The combination HDACi and ferroptosis inducers synergically suppresses growth both in vivo vitro. Mechanically, reduces suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, confirmed specifically targets HDAC1 promotes H3K27ac modification fat mass- obesity-associated gene (FTO) AlkB Homolog 5, RNA Demethylase (ALKBH5), results significant activation FTO ALKBH5. ALKBH5 N6-methyladenosine (m6A) on FSP1 mRNA, leading Crucially, lactylation HDAC1K412 essential for regulation. Both Vorinostat (SAHA) Trichostatin A (TSA) notably diminish comparison other inhibitors, exhibiting a consistent trend increasing susceptibility In conclusion, research reveals decreases sensitize can be promising therapeutic strategy CRC.

Language: Английский

Citations

2