Functions And Mechanisms Of LncFASA In Regulating Breast Cancer Ferroptosis Via Modulating PRDX1 Phase Separation

Ferroptosis,a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation,has a potential physiological function in tumor suppression.Recent studies have shown that long non-coding RNAs are involved in the regulation of ferroptosis in cancer cells,whereas its underlying mechanisms have not been fully elucidated.By bioinformatics screening from public databases,we identified one of the lnc RNAs,NR＿046677.1(renamed as Lnc FASA),which promotes ferroptosis process in breast cancer.Analysis of the clinical cohort showed that the low expression of Lnc FASA promotes malignant progression and poor prognosis of breast cancer.Through mass spectrometry and biochemical assays,we further verified that Lnc FASA interacts with the Ahpc-TSA domain of PRDX1,an antioxidant enzyme,disrupts the SLC7A11-GPX4 axis to promote ferroptosis in breast cancer.Further,cytoplasmic Lnc FASA blocks the peroxidase activity of PRDX1 by promoting the liquid-liquid phase separation,thereby upregulating intracellular lipid ROS levels and disrupting oxidative stress homeostasis,ultimately inhibiting the development of breast cancer.These results reveal the dynamic and functional complexity of cytoplasmic lnc RNAs in the regulation of cancer cells.Meanwhile,combined with animal models,this study further clarified the inhibitory effect of Lnc FASA on PRDX1-driven tumor proliferation in vivo,indicating that Lnc FASA may have an important potential as a new target for clinical diagnosis and treatment.Furthermore,analysis of the clinical cohort showed that breast cancer patients with high Lnc FASA expression exhibited lower SLC7A11 and GPX4 expression and higher PRDX1 phase separation droplets,revealing the important regulatory role of Lnc FASA as a tumor suppressor in tumor cell oxidative stress homeostasis.Taken together,this study demonstrates a novel mode of lnc RNA as a functional molecule to regulate kinase activity and oxidative stress homeostasis in tumor cells,providing new insights into understanding ferroptosis and disease progression.