Xi Zeng , Suwen Pang , Hong Lu , Jingchao Zhu , Ze Li , Ni Liu , Xifeng Zhang , Yun Wang , Zhifeng Wei
{"title":"Aloperine通过驱动TAS2R138-PLCβ/GAPDH轴介导的糖代谢重编程来抑制肠上皮细胞的铁下垂,从而改善放射性肠炎","authors":"Xi Zeng , Suwen Pang , Hong Lu , Jingchao Zhu , Ze Li , Ni Liu , Xifeng Zhang , Yun Wang , Zhifeng Wei","doi":"10.1016/j.bcp.2025.117292","DOIUrl":null,"url":null,"abstract":"<div><div>Radiation enteritis (RE) is a common side effect of radiotherapy, with no specific therapeutic agents available. <em>Sophora alopecuroides L.</em> (KDZ) has been used in China for many years to treat gastrointestinal disorders, and matrine, oxymatrine, and aloperine (ALO) are its main alkaloid components. We found that ALO significantly attenuated the damage of ionizing radiation (IR) to the viability of intestinal epithelial cells (IECs), outperforming matrine and oxymatrine. The IR-induced Fe<sup>2+</sup> accumulation, lipid peroxidation and down-regulated glutathione peroxidase 4 and solute carrier family 7 member 11 levels were restored, and ferroptosis but not apoptosis or necrosis was further indicated. Untargeted metabolomic analysis showed that ALO shifted the glucose flux from glycolysis to the hexosamine biosynthetic pathway to elevate the UDP-GlcNAc level. Notably, ALO could directly bind with taste 2 receptor member 138 (TAS2R138) as one of its potential targets, and promoted the activation of downstream signaling molecules phospholipase C β (PLCβ) and α-gustducin. Furthermore, ALO enhanced the association of PLCβ and GAPDH at MET56 and LYS271, and inhibiting the latter’s acetylation and activity <em>via</em> activating TAS2R138. In addition, after triggering the metabolic reprogramming, ALO promoted the <em>O/N</em>-glycosylation to prevent the lysosomal degradation of ferritin heavy chain 1 and transferrin receptor, modulating iron storage and transport, thus alleviating ferroptosis. <em>In vivo</em>, the above-mentioned effect and mechanisms of ALO were demonstrated using the model of RE in mice. Collectively, ALO activated TAS2R138 to promote the interaction of PLCβ and GAPDH to induce metabolic reprogramming and alleviate IR-induced ferroptosis of IECs to improve RE.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117292"},"PeriodicalIF":5.6000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Aloperine ameliorates radiation enteritis by driving the TAS2R138-PLCβ/GAPDH axis-mediated glucose metabolic reprogramming to inhibit ferroptosis in intestinal epithelial cells\",\"authors\":\"Xi Zeng , Suwen Pang , Hong Lu , Jingchao Zhu , Ze Li , Ni Liu , Xifeng Zhang , Yun Wang , Zhifeng Wei\",\"doi\":\"10.1016/j.bcp.2025.117292\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Radiation enteritis (RE) is a common side effect of radiotherapy, with no specific therapeutic agents available. <em>Sophora alopecuroides L.</em> (KDZ) has been used in China for many years to treat gastrointestinal disorders, and matrine, oxymatrine, and aloperine (ALO) are its main alkaloid components. We found that ALO significantly attenuated the damage of ionizing radiation (IR) to the viability of intestinal epithelial cells (IECs), outperforming matrine and oxymatrine. The IR-induced Fe<sup>2+</sup> accumulation, lipid peroxidation and down-regulated glutathione peroxidase 4 and solute carrier family 7 member 11 levels were restored, and ferroptosis but not apoptosis or necrosis was further indicated. Untargeted metabolomic analysis showed that ALO shifted the glucose flux from glycolysis to the hexosamine biosynthetic pathway to elevate the UDP-GlcNAc level. Notably, ALO could directly bind with taste 2 receptor member 138 (TAS2R138) as one of its potential targets, and promoted the activation of downstream signaling molecules phospholipase C β (PLCβ) and α-gustducin. Furthermore, ALO enhanced the association of PLCβ and GAPDH at MET56 and LYS271, and inhibiting the latter’s acetylation and activity <em>via</em> activating TAS2R138. In addition, after triggering the metabolic reprogramming, ALO promoted the <em>O/N</em>-glycosylation to prevent the lysosomal degradation of ferritin heavy chain 1 and transferrin receptor, modulating iron storage and transport, thus alleviating ferroptosis. <em>In vivo</em>, the above-mentioned effect and mechanisms of ALO were demonstrated using the model of RE in mice. Collectively, ALO activated TAS2R138 to promote the interaction of PLCβ and GAPDH to induce metabolic reprogramming and alleviate IR-induced ferroptosis of IECs to improve RE.</div></div>\",\"PeriodicalId\":8806,\"journal\":{\"name\":\"Biochemical pharmacology\",\"volume\":\"242 \",\"pages\":\"Article 117292\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S000629522500557X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S000629522500557X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Aloperine ameliorates radiation enteritis by driving the TAS2R138-PLCβ/GAPDH axis-mediated glucose metabolic reprogramming to inhibit ferroptosis in intestinal epithelial cells
Radiation enteritis (RE) is a common side effect of radiotherapy, with no specific therapeutic agents available. Sophora alopecuroides L. (KDZ) has been used in China for many years to treat gastrointestinal disorders, and matrine, oxymatrine, and aloperine (ALO) are its main alkaloid components. We found that ALO significantly attenuated the damage of ionizing radiation (IR) to the viability of intestinal epithelial cells (IECs), outperforming matrine and oxymatrine. The IR-induced Fe2+ accumulation, lipid peroxidation and down-regulated glutathione peroxidase 4 and solute carrier family 7 member 11 levels were restored, and ferroptosis but not apoptosis or necrosis was further indicated. Untargeted metabolomic analysis showed that ALO shifted the glucose flux from glycolysis to the hexosamine biosynthetic pathway to elevate the UDP-GlcNAc level. Notably, ALO could directly bind with taste 2 receptor member 138 (TAS2R138) as one of its potential targets, and promoted the activation of downstream signaling molecules phospholipase C β (PLCβ) and α-gustducin. Furthermore, ALO enhanced the association of PLCβ and GAPDH at MET56 and LYS271, and inhibiting the latter’s acetylation and activity via activating TAS2R138. In addition, after triggering the metabolic reprogramming, ALO promoted the O/N-glycosylation to prevent the lysosomal degradation of ferritin heavy chain 1 and transferrin receptor, modulating iron storage and transport, thus alleviating ferroptosis. In vivo, the above-mentioned effect and mechanisms of ALO were demonstrated using the model of RE in mice. Collectively, ALO activated TAS2R138 to promote the interaction of PLCβ and GAPDH to induce metabolic reprogramming and alleviate IR-induced ferroptosis of IECs to improve RE.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.