Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance DOI
Lijie Gu,

Yanhong Du,

Jianglei Chen

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 17, 2024

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin oxidative stress signaling. However, CRL3 function liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results rapid resolution steatosis obese mice. the remarkable resistance mice to developing does not lead overall metabolic improvement but causes systemic disturbances. Liver transcriptomics analysis identifies inactivation persistent activation nuclear factor erythroid 2–related 2 (NRF2) antioxidant defense pathway, which also reprograms lipid transcriptional network prevent TG storage. Furthermore, global metabolomics reveals NRF2 induces numerous NAD + -consuming aldehyde dehydrogenases increase cellular NADH/NAD ratio, a redox imbalance termed NADH reductive inhibits glycolysis–citrate–lipogenesis axis livers. As result, this NRF2-induced storage defect promotes ceramide accumulation, elevates circulating fatty acids, worsens vicious cycle. Hepatic accumulation restored, injury hyperglycemia are attenuated when abolished Cul3/Nrf2 double-knockout The steatosis, hyperglycemia, observed Keap1 with activation. In summary, our study defines critical role regulation demonstrates downstream overactivation maladaptation obesity resistance.

Язык: Английский

Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming DOI Creative Commons
Yang Chen,

Hongfei Yan,

Lirong Yan

и другие.

Cell Death and Disease, Год журнала: 2023, Номер 14(9)

Опубликована: Сен. 20, 2023

Abstract Aldehyde dehydrogenase 3A1 (ALDH3A1) is an NAD + -dependent enzyme that closely related to tumor development. However, its role in non-small-cell lung cancer (NSCLC) has not been elucidated. This study aimed clarify the mechanism of ALDH3A1 and identify potential therapeutic targets for NSCLC. Here, first time, we found expression could be induced by a hypoxic environment was highly expressed NSCLC tissue, especially some late-stage patients, associated with poor prognosis. In mechanistic terms, enhances glycolysis suppresses oxidative phosphorylation (OXPHOS) promote cell proliferation activating HIF-1α/LDHA pathway addition, results showed target β-elemene. can downregulated β-elemene inhibit enhance OXPHOS, thus suppressing vitro vivo. conclusion, hypoxia-induced energy metabolic status tumors efficacy β-elemene, providing new theoretical basis better clinical applications

Язык: Английский

Процитировано

22
Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression DOI Creative Commons
Janine M. DeBlasi, Aimee Falzone, Samantha Caldwell

и другие.

Cancer Research, Год журнала: 2023, Номер 83(12), С. 1953 - 1967

Опубликована: Апрель 16, 2023

Mutations in the KEAP1-NRF2 (Kelch-like ECH-associated protein 1-nuclear factor-erythroid 2 p45-related factor 2) pathway occur up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance therapy poor outcomes. Here, we developed murine alleles KEAP1 NRF2 mutations found human NSCLC comprehensively interrogated their impact on tumor initiation progression. Chronic stabilization by Keap1 or Nrf2 mutation was not sufficient induce tumorigenesis, even absence suppressors, p53 LKB1. When combined with KrasG12D/+, constitutive activation promoted early progression hyperplasia low-grade tumors but impaired advanced-grade tumors, which reversed deletion. Finally, overexpression mutant lines detrimental proliferation, viability, anchorage-independent colony formation. Collectively, these results establish context-dependence activity threshold for during tumorigenic process.

Язык: Английский

Процитировано

21
Peiminine triggers ferroptosis to inhibit breast cancer growth through triggering Nrf2 signaling DOI

Nian Yi,

Li Wang,

Zhongjun Jiang

и другие.

Tissue and Cell, Год журнала: 2024, Номер 87, С. 102323 - 102323

Опубликована: Фев. 4, 2024

Язык: Английский

Процитировано

8
Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function DOI Creative Commons
Jun Takahashi, Takafumi Suzuki,

Miu Sato

и другие.

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114104 - 114104

Опубликована: Апрель 1, 2024

Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in (NFE2L2) is frequently detected esophageal squamous cell carcinoma (ESCC), whereas KEAP1, a negative regulator NRF2, not. Here, we aspire to generate mouse model NRF2-activated ESCC using the cancer-derived

Язык: Английский

Процитировано

8
Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance DOI
Lijie Gu,

Yanhong Du,

Jianglei Chen

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 17, 2024

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin oxidative stress signaling. However, CRL3 function liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results rapid resolution steatosis obese mice. the remarkable resistance mice to developing does not lead overall metabolic improvement but causes systemic disturbances. Liver transcriptomics analysis identifies inactivation persistent activation nuclear factor erythroid 2–related 2 (NRF2) antioxidant defense pathway, which also reprograms lipid transcriptional network prevent TG storage. Furthermore, global metabolomics reveals NRF2 induces numerous NAD + -consuming aldehyde dehydrogenases increase cellular NADH/NAD ratio, a redox imbalance termed NADH reductive inhibits glycolysis–citrate–lipogenesis axis livers. As result, this NRF2-induced storage defect promotes ceramide accumulation, elevates circulating fatty acids, worsens vicious cycle. Hepatic accumulation restored, injury hyperglycemia are attenuated when abolished Cul3/Nrf2 double-knockout The steatosis, hyperglycemia, observed Keap1 with activation. In summary, our study defines critical role regulation demonstrates downstream overactivation maladaptation obesity resistance.

Язык: Английский

Процитировано

7