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Chemico-Biological Interactions

Chemico-Biological Interactions

IF: 4.7
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NR1I3 inhibits colorectal cancer growth by enhancing PCK1-mediated gluconeogenesis

Published:8 September 2025 DOI: 10.1016/j.cbi.2025.111734
Huanying Shi , Zimei Wu , Jiafeng Liu , Tianxiao Wang , Zhengchuan Niu , Wenxin Zhang , Bicui Chen , Xiang Mao , Yuxin Huang , Jiyifan Li , Huijie Qi , Xinhai Wang , Lu Chen , Qunyi Li

Abstract

There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT?PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
CITCO 338404-52-7 C19H12Cl3N3OS 71 suppliers $20.00-$2200.00
CITCO 338404-52-7 C19H12Cl3N3OS 71 suppliers $20.00-$2200.00
CITCO 338404-52-7 C19H12Cl3N3OS 71 suppliers $20.00-$2200.00
CITCO 338404-52-7 C19H12Cl3N3OS 71 suppliers $20.00-$2200.00
3-Mercaptopicolinic Acid, Hydrochloride 320386-54-7 C6H6ClNO2S 68 suppliers $12.00-$2200.00
3-Mercaptopicolinic Acid, Hydrochloride 320386-54-7 C6H6ClNO2S 68 suppliers $12.00-$2200.00
3-Mercaptopicolinic Acid, Hydrochloride 320386-54-7 C6H6ClNO2S 68 suppliers $12.00-$2200.00
3-Mercaptopicolinic Acid, Hydrochloride 320386-54-7 C6H6ClNO2S 68 suppliers $12.00-$2200.00

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