Emerging evidence suggests that long non-coding RNAs(lncRNAs)play crucial roles in ferroptosis regulation,yet the detailed mechanisms remain largely elusive.In this study,we identify LINC00942,a ferroptosis-associated...Emerging evidence suggests that long non-coding RNAs(lncRNAs)play crucial roles in ferroptosis regulation,yet the detailed mechanisms remain largely elusive.In this study,we identify LINC00942,a ferroptosis-associated lncRNA,which localizes to mitochondria and coordinates ferroptosis and tumorigenesis by modulating mitochondrial function.Bioinformatic analysis establishes that LINC00942 is specifically overexpressed in hepatocellular carcinoma(HCC),and its high expression is closely associated with poor patient prognosis.Both in vitro and in vivo experiments demonstrate that LINC00942 promotes HCC cell proliferation,migration,and invasion.Furthermore,suppression of LINC00942 disrupts mitochondrial function,impairs energy metabolism,and increases mitochondrial lipid peroxidation and reactive oxygen species(ROS)levels,rendering HCC cells more susceptible to ferroptosis.Mechanistically,LINC00942 interacts with G-rich sequence factor 1(GRSF1)and subsequently translocates to the mitochondria.Within mitochondria,LINC00942 facilitates the binding of GRSF1 to complex I mRNA,thereby enhancing the translation efficiency of complex I subunits.The resulting upregulation of complex I protein levels strengthens its enzymatic activity and promotes mitochondrial oxidative phosphorylation,while concurrently suppressing ferroptosis.In addition,DNA demethylation and CREB1 contribute to the transcriptional activation of LINC00942 in HCC.Notably,administration of GalNAc-conjugated siRNA targeting LINC00942 effectively suppresses tumor growth in orthotopic xenograft models.Collectively,these findings underscore the oncogenic function of LINC00942 through the modulation of mitochondrial bioenergetics and ferroptosis,highlighting it as a promising therapeutic target for HCC.展开更多
基金supported by National Key Research and Development Program of China(2024YFC3405900)the National Natural Science Foundation of China(82121004)。
文摘Emerging evidence suggests that long non-coding RNAs(lncRNAs)play crucial roles in ferroptosis regulation,yet the detailed mechanisms remain largely elusive.In this study,we identify LINC00942,a ferroptosis-associated lncRNA,which localizes to mitochondria and coordinates ferroptosis and tumorigenesis by modulating mitochondrial function.Bioinformatic analysis establishes that LINC00942 is specifically overexpressed in hepatocellular carcinoma(HCC),and its high expression is closely associated with poor patient prognosis.Both in vitro and in vivo experiments demonstrate that LINC00942 promotes HCC cell proliferation,migration,and invasion.Furthermore,suppression of LINC00942 disrupts mitochondrial function,impairs energy metabolism,and increases mitochondrial lipid peroxidation and reactive oxygen species(ROS)levels,rendering HCC cells more susceptible to ferroptosis.Mechanistically,LINC00942 interacts with G-rich sequence factor 1(GRSF1)and subsequently translocates to the mitochondria.Within mitochondria,LINC00942 facilitates the binding of GRSF1 to complex I mRNA,thereby enhancing the translation efficiency of complex I subunits.The resulting upregulation of complex I protein levels strengthens its enzymatic activity and promotes mitochondrial oxidative phosphorylation,while concurrently suppressing ferroptosis.In addition,DNA demethylation and CREB1 contribute to the transcriptional activation of LINC00942 in HCC.Notably,administration of GalNAc-conjugated siRNA targeting LINC00942 effectively suppresses tumor growth in orthotopic xenograft models.Collectively,these findings underscore the oncogenic function of LINC00942 through the modulation of mitochondrial bioenergetics and ferroptosis,highlighting it as a promising therapeutic target for HCC.
