Targeting the ferroptosis crosstalk:novel alternative strategies for the treatment of major depressive disorder

Depression is a major contributor to poor global health and disability,with a recently increasing incidence.Although drug therapy is commonly used to treat depression,conventional antidepressant drugs have several disadvantages,including slow onset,low response rates and severe adverse effects.Therefore,developing effective therapies for depression remains challenging.Although various aetiological theories of depression exist,the underlying mechanisms of depression are complex,and further research is crucial.Moreover,oxidative stress(OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis.Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders,and investigation of the mediators involved in these processes has emerged as a prominent and active research direction.One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression,and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo,suggesting an important role of ferroptosis in the pathogenesis of depression.Hence,our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved,specifically concerning ferroptosis and OS in the context of depression,along with promising prospects for using molecular mediators to target ferroptosis.We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression,most notably reactive oxygen species and iron overload.Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders,delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Crosstalk between glioblastoma and tumor microenvironment drives proneural–mesenchymal transition through ligand-receptor interactions

Glioblastoma(GBM)is the most common intrinsic and aggressive primary brain tumor in adults,with a median survival of approximately 15 months.GBM heterogeneity is considered responsible for the treatment resistance and unfavorable prognosis.Proneural-mesenchymal transition(PMT)represents GBM malignant progression and recurrence,which might be a breakthrough to understand GBM heterogeneity and overcome treatment resistance.PMT is a complicated process influenced by crosstalk between GBM and tumor microenvironment,depending on intricate ligand-receptor interactions.In this review,we summarize the autocrine and paracrine pathways in the GBM microenvironment and related ligand-receptor interactions inducing PMT.We also discuss the current therapies targeting the PMT-related autocrine and paracrine pathways.Together,this review offers a comprehensive understanding of the failure of GBM-targeted therapy and ideas for future tendencies of GBM treatment.

Single-cell analyses identify anaphase-promoting complex subunit 11 as a switch controlling neuronal differentiation of glioblastoma cells

Glioblastoma(GBM)is the most common and lethal malignancy in the central nervous system.1 One of the major difficulties in treatment is that the initial clinical diagnosis of GBM is already WHO grade IV,without recognizable lower-grade precursor lesions.Copy number variations(CNVs)were found to appear in malignant cells several years before the initial diagnosis of GBM.2 Less differentiation and more aggressive phenotypes were observed in GBM cells with a higher degree of CNVs.3 Additionally,CNVs provide more accurate stratification of clinical outcomes than does the WHO grade system.4 Therefore,we reasoned that differentially expressed genes(DEGs)among GBM cells with different CNV statuses would be significant for the aggressiveness of GBM.Here we leveraged the single-cell RNA-sequencing(scRNA-seq)to construct the CNV profile of GBM at single-cell resolution,divided GBM cells into different clusters according to their CNV statuses,and investigated the molecular functions of DEGs among GBM clusters.Through a series of experiments,we identified anaphase-promoting complex subunit 11(ANAPC11)as a switch controlling the neuronal differentiation of GBM cells,providing a novel alternative for the development of differentiation-inducing therapy to overcome GBM.