Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechani...Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.展开更多
Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In t...Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue(cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.展开更多
基金supported by the Central Government-Guided Local Science and Technology Development Fund Project(Science and Technology Innovation Base Project)(Grant No.236Z7749G)Hebei Provincial Precision Medicine Innovation and Development Joint Fund Incubation Project(Grant No.H2025206547)Hebei Provincial Basic Research Special Youth Science Fund Project(Grant No.H2025206274).
文摘Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.
基金supported by the National Natural Science Foundation of China,No. 81671164 (to SHQ)the Natural Science Foundation of Jiangsu Province of China,No. BK20211348 (to SHQ)Xuzhou Basic Research Program,No. KC21030 (to LYH)。
文摘Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue(cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.
