The cystine/glutamate antiporter SLC7A11, as the key regulator of ferroptosis, functions to transport cystine for glutathione biosynthesis and antioxidant defense. Accumulating evidence has shown that SLC7A11 is overexpressed in multiple human cancers and promotes tumor growth and progression. However, the exact mechanism underlying this key protein remains unclear. In this study, we confirmed that SLC7A11 is S-palmitoylated in glioblastoma, and this modification is required for SLC7A11 protein stability. Moreover, we revealed that ZDHHC8, a member of the protein palmitoyl transferases (PATs), catalyzes S-palmitoylation of SLC7A11 at Cys327, thereby decreasing the ubiquitination level of SLC7A11. Furthermore, AMPKα1 directly phosphorylates ZDHHC8 at S299, strengthening the interaction between ZDHHC8 and SLC7A11, leading to SLC7A11 S-palmitoylation and deubiquitination. Functional investigations showed that ZDHHC8 knockdown impairs glioblastoma (GBM) cell survival via promoting intracellular ferroptosis events, which could be largely rescued by ectopic expression of SLC7A11. Clinically, ZDHHC8 expression positively correlates with SLC7A11 and AMPKα1 expression in clinical glioma specimens. This study underscores that ZDHHC8-mediated SLC7A11 S-palmitoylation is critical for ferroptosis resistance during GBM tumorigenesis, indicating a novel treatment strategy for GBM. 

AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma.

Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechansisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders. 

Immunosenescence and Inflammaging: Mechanisms and Role in Diseases

With a limited number of genes, cells achieve remarkable diversity. This is to a large extent achieved by chemical posttranslational modifications of proteins. Amongst these are the lipid modifications that have the unique ability to confer hydrophobicity. The last decade has revealed that lipid modifications of proteins are extremely frequent and affect a great variety of cellular pathways and physiological processes. This is particularly true for S-acylation, the only reversible lipid modification. The enzymes involved in S-acylation and deacylation are only starting to be understood, and the list of proteins that undergo this modification is ever-increasing. We will describe the state of knowledge on the enzymes that regulate S-acylation, from their structure to their regulation, how S-acylation influences target proteins, and finally will offer a perspective on how alterations in the balance between S-acylation and deacylation may contribute to disease. 

Refining S-acylation: Structure, regulation, dynamics, and therapeutic implications

The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity of the host immune cells. However, various local and systemic mechanisms of immunosuppression operate in cancer patients. Tumor-associated immunosuppression involves deregulation of many components of immunity, including a decrease in the number of T lymphocytes (lymphopenia), an increase in the levels or ratios of circulating and tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)], as well as defective functions of subsets of antigen-presenting, helper and effector immune cell due to altered expression of various soluble and membrane proteins (receptors, costimulatory molecules, and cytokines). In this review, we specifically focus on data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related immunosuppression at baseline and the prognostic significance of different subsets of circulating and tumor-infiltrating immune cells (lymphocytes, CD4+ and CD8+ T cells, Tregs, natural killer (NK) cells, neutrophils, macrophages, MDSCs, and dendritic cells), including neutrophil-to-lymphocyte ratio (NLR), focus on the immune landscape and prognostic significance of isocitrate dehydrogenase (IDH)-mutant gliomas, proneural, classical and mesenchymal molecular subtypes, and highlight the features of immune surveillance in the brain. All attempts to identify a reliable prognostic immune marker in glioblastoma tissue have led to contradictory results, which can be explained, among other things, by the unprecedented level of spatial heterogeneity of the immune infiltrate and the significant phenotypic diversity and (dys)functional states of immune subpopulations. High NLR is one of the most repeatedly confirmed independent prognostic factors for shorter overall survival in patients with glioblastoma and carcinoma, and its combination with other markers of the immune response or systemic inflammation significantly improves the accuracy of prediction; however, more prospective studies are needed to confirm the prognostic/predictive power of NLR. We call for the inclusion of dynamic assessment of NLR and other blood inflammatory markers (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, and systemic immune response index) in all neuro-oncology studies for rigorous evaluation and comparison of their individual and combinatorial prognostic/predictive significance and relative superiority.

Systemic and local immunosuppression in glioblastoma and its prognostic significance

Aquaporin 4 (AQP4) facilitates the transport of reactive oxygen species (ROS). Both cancer cells and the ionizing radiation microenvironment can induce posttranslational modifications (PTMs) in AQP4, which may affect its permeability to ROS. Because this ROS diffusion process is rapid, microscopic, and instantaneous within and outside cells, conventional experimental methods are inadequate for elucidating the molecular mechanisms involved. In this study, computational methods were employed to investigate the permeability of exogenous ROS mediated by radiation in AQP4 at a molecular scale. We constructed a simulation system incorporating AQP4 and AQP4-Cysp13 in a complex lipid environment with ROS. Long-timescale molecular dynamics simulations were conducted to assess the structural stability of both AQP4 and AQP4-Cysp13. Free energy calculations were utilized to determine the ROS transport capability of the two AQP4 proteins. Computational electrophysiology and channel structural analysis quantitatively evaluated changes in ROS transport capacity under various radiation-induced transmembrane voltage microenvironments. Our findings demonstrate the distinct transport capabilities of AQP4 channels for water molecules and various types of ROS and reveal a decrease in transport efficiency when AQP4 undergoes palmitoylation modification. In addition, we have simulated the radiation-induced alteration of cell membrane voltage, which significantly affected the ROS transport capacity. We propose that this research will enhance the understanding of the molecular mechanisms governing the transport of exogenous ROS by AQP4 and elucidate the influence of palmitoylation on ROS transport. This study will also help clarify how different structural features of AQP4 affect the transport of exogenous ROS mediated by radiotherapy, thereby providing a theoretical molecular basis for the development of new treatment strategies that combine with radiotherapy. 

Effect of AQP4 and its palmitoylation on the permeability of exogenous reactive oxygen species: Insights from computational study

Abstract Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma). 

The Role of Beta2-Microglobulin in Central Nervous System Disease

OBJECTIVE TERT: is the most frequently mutated gene in adult glioblastomas (GBMs) defined by the 2021 World Health Organization classification system. The present study aims to explore differences in clinical characteristics and immune microenvironment between TERT mutant and wild-type GBM.Three GBM-related cohorts consisting of 205 GBM patients in our cohort, 463 GBM patients without immune checkpoint inhibitor(ICI) therapy and 1465 tumour patients (including 92 GBM cases) receiving ICI treatment in the MSK cohort were included. Retrospective analysis and immunohistochemistry assay were used for investigating the local (including tumour cells, local immune cells, and seizures) and systemic (including circulating immune cells, coagulation-related functions, and prognosis) effects of TERT mutations. Besides, differences in genetic alterations and immunotherapy responses between TERT mutant and wild-type GBMs were also explored.We found that TERT mutant and wild-type GBMs possessed similar initial clinic symptoms, circulating immune microenvironment and immunotherapy response. With respect to that in TERT wild-type GBMs, mutations in TERT resulted in higher levels of tumour-infiltrating neutrophils, prolonged coagulation time, worse chemotherapy response and poorer overall survival.Mutations in TERT alter the local immune environment and decrease the sensitivity of GBM to chemotherapy. 

TERT mutations-associated alterations in clinical characteristics, immune environment and therapy response in glioblastomas

Adult gliomas are divided into isocitrate dehydrogenase (IDH) wild‐type and IDH mutant subtypes according to the new 2021 World Health Organization classification system. However, the local and systemic effects of IDH mutations on primary glioma patients are not well illustrated. Retrospective analysis, immune‐cell infiltration analysis, meta‐analysis, and immunohistochemistry assay were applied in the present study. The results from our cohort showed that IDH mutant gliomas own a lower proliferating rate compared to that in wild‐type gliomas. Patients with mutant IDH exhibited a higher frequency of seizures in both our cohort and the cohort from the meta‐analysis. Mutations in IDH result in lower levels of intra‐tumour but higher levels of circulating CD4+ and CD8+ T lymphocytes. Levels of neutrophils in both intra‐tumour and circulating blood were lower in IDH mutant gliomas. Moreover, IDH mutant glioma patients receiving radiotherapy in combination with chemotherapy exhibited better overall survival with respect to radiotherapy alone. Mutations in IDH alters the local and circulating immune microenvironment, and increases the sensitivity of tumour cell to chemotherapy.

Local and systemic effects of IDH mutations on primary glioma patients

Current knowledge of protein palmitoylation in gliomas

Glioma is the most common and aggressive tumor in the adult brain. Recent studies have indicated that Zinc finger DHHC-type palmitoyltransferases (ZDHHCs) play vital roles in regulating the progression of glioma. ZDHHC15, a member of the ZDHHCs family, participates in various physiological activities in the brain. However, the biological functions and related mechanisms of ZDHHC15 in glioma remain poorly understood.Data from multiple glioma-associated datasets were used to investigate the expression profiles and potential biological functions of ZDHHC15 in glioma. Expression of ZDHHC15 and its association with clinicopathological characteristics in glioma were validated by quantitative reverse transcription PCR (RT-qPCR) and immunohistochemical experiments. GO enrichment analysis, KEGG analysis, GSEA analysis, CCK-8, EdU, transwell, and western blotting assays were performed to confirm the functions and mechanism of ZDHHC15 in glioma. Moreover, we performed Kaplan-Meier analysis and Cox progression analysis to explore the prognostic significance of ZDHHC15 in glioma patients.ZDHHC15 expression was significantly up-regulated in glioma and positively associated with malignant phenotypes. Results from the GO and KEGG enrichment analysis revealed that ZDHHC15 was involved in regulating cell cycle and migration. Knockdown of ZDHHC15 inhibited glioma cell proliferation and migration, while overexpression of ZDHHC15 presented opposite effects on glioma cells. Besides, results from GSEA analysis suggested that ZDHHC15 was enriched in STAT3 signaling pathway. Knockdown or overexpression of ZDHHC15 indeed affected the activation of STAT3 signaling pathway. Additionally, we identified ZDHHC15 as an independent prognostic biomarker in glioma, and higher expression of ZDHHC15 predicted a poorer prognosis in glioma patients.Our findings suggest that ZDHHC15 promotes glioma malignancy and can serve as a novel prognostic biomarker for glioma patients. Targeting ZDHHC15 may be a promising therapeutic strategy for glioma. 

https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-023-10883-6

ZDHHC15 promotes glioma malignancy and acts as a novel prognostic biomarker for patients with glioma

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