Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form...Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form of regulated cell death,has garnered considerable attention due to its lethal effect on tumor cells.However,the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma(HCC)effects remains poorly understood.This study investigated the impact of esculetin on HCC cells both in vitro and in vivo.The findings indicate that esculetin effectively inhibited the growth of HCC cells.Importantly,esculetin promoted the accumulation of intracellular Fe^(2+),leading to an increase in ROS production through the Fenton reaction.This event subsequently induced lipid peroxidation(LPO)and triggered ferroptosis within the HCC cells.The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde(MDA)levels,the depletion of glutathione peroxidase(GSH-Px)activity,and the disruption of mitochondrial morphology.Notably,the inhibitor of ferroptosis,ferrostatin-1(Fer-1),attenuated the anti-tumor effect of esculetin in HCC cells.Furthermore,the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells.Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4,consequently alleviating esculetin-induced ferroptosis.In conclusion,this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis,thereby triggering ferroptosis in HCC cells.These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.展开更多
BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related mortality worldwide,primarily due to tumor heterogeneity and treatment resistance.The leucine-rich repeat-containing protein 19(LRRC19)has been lin...BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related mortality worldwide,primarily due to tumor heterogeneity and treatment resistance.The leucine-rich repeat-containing protein 19(LRRC19)has been linked to immune regulation and tumor suppression,yet its specific role in CRC remains poorly understood.AIM To investigate the tumor-suppressive role of LRRC19 in CRC,focusing on cell cycle,immune microenvironment,and chemotherapy response.METHODS Bioinformatics analyses of Gene Expression Omnibus and The Cancer Genome Atlas databases identified differentially expressed genes in CRC.LRRC19 exp-ression was validated in CRC tissues and cell lines by quantitative PCR,immuno-histochemistry,and Western blotting.Functional assays,including proliferation,soft agar colony formation,flow cytometry,and xenograft models,assessed biological effects.Mechanistic studies with dual-luciferase reporter assays,molecular docking,and drug sensitivity testing explored LRRC19’s interaction with the cyclin-dependent kinase 6(CDK6)/E2F1 axis and oxaliplatin(OXA)response.Single-cell sequencing and immune infiltration analyses assessed its impact on the immune microenvironment.RESULTS LRRC19 expression was significantly downregulated in CRC and associated with poor prognosis.Overexpression of LRRC19 inhibited CRC cell proliferation,induced G0/G1 phase arrest,and suppressed tumor growth in vivo.Mechanistically,LRRC19 suppressed CDK6 transcription by downregulating E2F1,leading to cell cycle arrest.Additionally,LRRC19 promoted immune cell infiltration,particularly B cells and CD4+T cells,while decreasing immunosuppressive cells.LRRC19 also sensitized CRC cells to OXA,enhancing chemotherapy efficacy.CONCLUSION LRRC19 suppresses CRC by targeting the CDK6/E2F1 axis,modulating the immune microenvironment,and enhancing chemotherapy sensitivity,making it a promising therapeutic target for precision medicine in CRC.展开更多
基金supported by the Natural Science Foundations of Fujian Province(Nos.2021J05063 and 2023J01541)a startup grant for High-level Talents of Fujian Medical University(No.XRCZX2021014)。
文摘Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form of regulated cell death,has garnered considerable attention due to its lethal effect on tumor cells.However,the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma(HCC)effects remains poorly understood.This study investigated the impact of esculetin on HCC cells both in vitro and in vivo.The findings indicate that esculetin effectively inhibited the growth of HCC cells.Importantly,esculetin promoted the accumulation of intracellular Fe^(2+),leading to an increase in ROS production through the Fenton reaction.This event subsequently induced lipid peroxidation(LPO)and triggered ferroptosis within the HCC cells.The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde(MDA)levels,the depletion of glutathione peroxidase(GSH-Px)activity,and the disruption of mitochondrial morphology.Notably,the inhibitor of ferroptosis,ferrostatin-1(Fer-1),attenuated the anti-tumor effect of esculetin in HCC cells.Furthermore,the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells.Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4,consequently alleviating esculetin-induced ferroptosis.In conclusion,this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis,thereby triggering ferroptosis in HCC cells.These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.
基金Supported by the Natural Science Foundation of Zhejiang Province,No.LY22H160005。
文摘BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related mortality worldwide,primarily due to tumor heterogeneity and treatment resistance.The leucine-rich repeat-containing protein 19(LRRC19)has been linked to immune regulation and tumor suppression,yet its specific role in CRC remains poorly understood.AIM To investigate the tumor-suppressive role of LRRC19 in CRC,focusing on cell cycle,immune microenvironment,and chemotherapy response.METHODS Bioinformatics analyses of Gene Expression Omnibus and The Cancer Genome Atlas databases identified differentially expressed genes in CRC.LRRC19 exp-ression was validated in CRC tissues and cell lines by quantitative PCR,immuno-histochemistry,and Western blotting.Functional assays,including proliferation,soft agar colony formation,flow cytometry,and xenograft models,assessed biological effects.Mechanistic studies with dual-luciferase reporter assays,molecular docking,and drug sensitivity testing explored LRRC19’s interaction with the cyclin-dependent kinase 6(CDK6)/E2F1 axis and oxaliplatin(OXA)response.Single-cell sequencing and immune infiltration analyses assessed its impact on the immune microenvironment.RESULTS LRRC19 expression was significantly downregulated in CRC and associated with poor prognosis.Overexpression of LRRC19 inhibited CRC cell proliferation,induced G0/G1 phase arrest,and suppressed tumor growth in vivo.Mechanistically,LRRC19 suppressed CDK6 transcription by downregulating E2F1,leading to cell cycle arrest.Additionally,LRRC19 promoted immune cell infiltration,particularly B cells and CD4+T cells,while decreasing immunosuppressive cells.LRRC19 also sensitized CRC cells to OXA,enhancing chemotherapy efficacy.CONCLUSION LRRC19 suppresses CRC by targeting the CDK6/E2F1 axis,modulating the immune microenvironment,and enhancing chemotherapy sensitivity,making it a promising therapeutic target for precision medicine in CRC.
