Yuanyuan Chen

Targeting cuproptosis for cancer therapy is hindered by an incomplete understanding of the intrinsic defense networks through which tumor cells mobilize to evade this fate, particularly under therapeutic stress such as radiotherapy. Here, we identify VPS34‐mediated copper homeostasis as a critical anticuproptotic process through a genome‐wide CRISPR activation screen. PRMT5 directly methylated VPS34 at Arg174 and inhibited K48‐linked polyubiquitination and proteasomal degradation of VPS34 by recruiting the deubiquitinase USP10. This stabilization increased the cuproptotic defense of tumor cells by promoting autophagic degradation of the copper importer SLC31A1 and plasma membrane translocation of the exporter ATP7A, thereby reducing the intracellular copper load. Functional analysis and clinical correlation revealed that the PRMT5‐VPS34 axis is robustly activated by radiation stress and is necessary for adaptive radioresistance. The inhibition of PRMT5 or VPS34 expression suppressed tumor growth and enhanced the sensitivity of tumors to radiotherapy by unleashing latent copper cytotoxicity both in vitro and in vivo. Together, our findings identify the PRMT5‐VPS34 axis as a therapeutic target for sensitizing refractory cancers to radiotherapy.

Radioresistance is a main reason for treatment failure in patients with small cell lung cancer (SCLC). Consequently, it is important to determine the key mechanism and explore effective strategies to prevent SCLC radioresistance. We use an unbiased CRISPR screen to identify GSDME, a member of the Gasdermin (GSDM) family, as a critical driver of radiosensitivity in SCLC. Furthermore, we identify mTORC2 facilitates SCLC radioresistance by inhibiting GSDME‐N‐mediated pyroptosis. Mechanistically, mTORC2 phosphorylates GSDME‐N at serine 114 (S114), promoting the recruitment of the CUL4B‐RBBP4 E3 ubiquitin ligase complex. This complex mediates K48‐linked ubiquitination of GSDME‐N at lysine 41 (K41), leading to its proteasomal degradation. Clinically, elevated mTORC2 is linked to an unfavorable prognosis in SCLC patients. The study reveals mTORC2 phosphorylates GSDME‐N and promotes its Cullin4B‐mediated proteasomal degradation to suppress pyroptosis and drive radioresistance in SCLC.

Background: Magnetic resonance image (MRI)‐guided radiotherapy can optimize the therapeutic outcomes of brain glioma patients, as it adjusts to tumor changes in the course of radiation treatment. This study evaluates the dynamic changes of tumors and the feasibility of implementing MRI‐guided online adaptive radiotherapy (MRIgOART) for the treatment of brain glioma. Patients & Methods: This observational prospective cohort study involved patients with brain glioma treated using 1.5 T MR‐Linac from 2021 to 2023. MRIgOART can correct treatment errors and evaluate treatment response through adapt‐to‐position (ATP) and adapt‐to‐shape (ATS) strategies. Dice similarity coefficient (DSC), absolute/relative volume (Vrel), and Hausdorff distance (HD) metrics were used to quantify tumor changes. The covariables subjected to evaluation included: surgical resection extent, 1p/19q status, telomerase reverse transcriptase (TERT) mutation status, O6‐methylguanine‐DNA‐methyltransferase (MGMT) methylation status, and isocitrate dehydrogenase (IDH) mutation status. ART and non‐ART treatment plans were comparatively analyzed based on target coverage and dose constraints for normal brain tissue. The pattern of failure, as the primary endpoint, was evaluated in this study. Secondary endpoints of the study consisted of overall survival (OS) and progression‐free survival (PFS), assessed according to treatment schedules. Results: The cohort comprised 57 patients. The patients with an interval longer than 10 days from simulation to the Fx1 exhibited more significant tumor changes ( p < 0.001). The tumor volume showed a gradual reduction during the treatment, whereas the alterations in its location and shape became increasingly evident over time. Multivariate analyses identified associations between prognosis and HD, in addition to a relationship between the extent of surgical resection and DSC. ATS was utilized in 52.6% of patients at least once during treatment, with a higher frequency in TERT wild‐type patients ( p = 0.013). MRIgOART treatment plans achieved superior target conformality, adequate coverage, and effective sparing of OARs. High‐grade glioma (HGG) patients exhibited median PFS of 13 months (95% CI, 10.2–15.8 months) and OS of 28 months (95% CI, 23.3–32.7 months). Failure analysis revealed 58.9% in‐field, 17.6% marginal, and 23.5% distant recurrences, with IDH mutation status associated with failure patterns. Conclusion: Preliminary findings in patients with HGG suggest a lower incidence of recurrences within the radiation field and indicate promising outcomes associated with MRIgOART. However, these observations require further validation through comparative studies.

Background: The global burden of central nervous system (CNS) cancers is rising unevenly. Existing studies lack a framework linking macro trends to underlying drivers across scales. Methods: We constructed a “macro-meso-micro” framework, integrating Global Burden of Disease 2021 data (macro perspective) and US SEER registry data (meso perspective). Global/regional/national incidence and mortality trends (1990-2021) were analyzed using descriptive statistics and Bayesian models, alongside subtype-specific clinical patterns. Results: The global age-standardized incidence rate (ASIR) increased from 3.82 to 4.28 per 100,000 population (1990-2021), while the age-standardized mortality rate (ASMR) declined slowly (3.08-3.06), revealing a core “incidence-mortality decoupling.” Incidence correlated positively with the socio-demographic index (SDI), but some high-SDI regions achieved superior mortality control, indicating healthcare disparities. SEER data clarified that this plateau was driven by the dismal survival of aggressive subtypes like glioblastoma (GBM), contrasting sharply with the rising detection of benign/low-grade tumors (eg, meningioma). For GBM, standard care has reached a low therapeutic ceiling, with most patients relapsing into a treatment void. Conclusions: CNS cancer burden evolution resulted from multi-scale diagnostic, therapeutic, and biological interactions. Our framework connected macro trends, meso subtype heterogeneity, and micro resistance mechanisms, pinpointing the conquest of therapy-resistant, high-grade tumors (especially GBM) as the central challenge. A translational pathway of “macro surveillance for target identification—clinical problem definition—mechanistic research for breakthrough” was proposed to guide future intervention.

Purpose: The optimal timing of Tumor Treating Fields (TTFields) with concurrent chemoradiotherapy (CRT) in high-grade glioma (HGG) remains unclear. This study compared survival and recurrence patterns between concurrent TTFields with CRT (CC-TTF) and sequential TTFields after CRT (S-TTF) in Chinese HGG patients. Methods: In this multi-center retrospective study, 114 HGG patients (70 CC-TTF, 44 S-TTF) treated between 2018-2023 were analyzed. Progression-free survival (PFS), overall survival (OS), and recurrence patterns were assessed using Kaplan-Meier methods, log-rank tests, and Cox regression. Results: The S-TTF group had a considerably longer median PFS (17.9 vs. 13.2 months, p=0.0175) and improved OS (33.4 vs. 21.6 months, p=0.1355) than the CC-TTF group for isocitrate dehydrogenase(IDH) wild-type patients. Recurrent IDH wild-type patients in the S-TTF group had better PFS (12.62 vs. 8.44 months, p=0.0363) and a longer OS (23.7 vs. 18.0 months, p=0.0666). Higher baseline Karnofsky Performance Status (KPS) scores (HR=0.66, p=0.0001) and longer TTFields duration (HR=0.95, p=0.0177) were found to be favorable prognostic factors for OS. However, delayed TTFields initiation (≥2.22 months post-diagnosis) was associated with increased distant progression (p = 0.0388). The recurrence patterns differed significantly between groups, with the S-TTF group having higher distant metastatic rates (34% vs. 26%). Conclusion: Sequential TTFields after CRT may increase PFS in IDH wild-type HGG patients compared to concurrent TTFields with CRT; however, OS advantages need to be validated. Distant recurrence was more prevalent with delayed TTFields commencement, indicating that timing affects illness development patterns. These findings lend support to future investigations aimed at optimizing TTFields inclusion into HGG therapy procedures.

The COVID‐19 pandemic has reshaped global health; however, the long‐term burden of long COVID remains poorly understood, especially in low‐ and middle‐income countries (LMICs), where limited surveillance and data gaps may obscure a substantial and sustained impact. Using the Global Burden of Disease (GBD) 2021 framework, we previously assessed the direct COVID‐19 burden—including incidence, prevalence, mortality, and disability‐adjusted life‐years (DALYs)—across 920 locations during 2020–2021. In this study, we focus on years lived with disability (YLDs), particularly in 2021, as a potential early indicator to identify locations and populations that may be at higher risk of long COVID burden in subsequent years (e.g., 2022–2023). We also examine patterns of inequality to highlight vulnerable groups. Our findings are consistent with multiple large‐scale studies on long COVID and suggest that YLDs may serve as a useful early proxy for ongoing burden. Importantly, we identify notably higher age‐standardized YLD rates in LMICs—especially in Sub‐Saharan Africa and in parts of South Asia and Eastern Europe. These areas, previously underexplored in long COVID research, might be particularly susceptible to its effects. Among the top 10 countries with the highest age‐standardized YLD rates in 2021, 80% fell within the low, low‐middle, and middle Socio‐demographic Index (SDI) categories. These high age‐standardized YLD rates may point to systemic vulnerabilities and entrenched structural health disparities, indicating a potential for considerable and enduring long COVID burden that could persist to the present day in the absence of targeted interventions. Furthermore, our inequality analysis underscores that while both advantaged and disadvantaged groups in LMICs require attention, the most disadvantaged groups warrant special focus due to their more severe resource constraints and restricted capacity for resilience‐building. Overall, this study supports calls for stronger surveillance, expanded access to rehabilitation, and better integration of long COVID care into universal health coverage. Continued GBD updates will be essential for monitoring trends and guiding responsive public health strategies.

Although the COVID‐19 pandemic has profoundly reshaped global health systems, a comprehensive and standardized quantification of its direct health burden across multiple spatial scales, particularly during its initial and most severe phases in 2020 and 2021, has remained lacking. Here, we present the first global‐to‐local estimation of the direct COVID‐19 burden during this period based on a repeated cross‐sectional design and secondary analysis of population‐level data using the Global Burden of Disease (GBD) 2021 analytical framework. We evaluated key measures of health burden for each year separately and assessed temporal changes to capture evolving patterns and disparities across 920 locations spanning five spatial hierarchies: global, regional, national, subnational, and local. The analysis includes 204 countries and territories, 77 international regions (e.g., the Commonwealth), 20 subnational regions (e.g., North England), and 618 local units (e.g., London). By integrating coarse‐grained (e.g., global and regional) and fine‐grained (e.g., national and local) estimates, we identified substantial spatial and socioeconomic inequalities in incidence, prevalence, mortality, disability‐adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs). Both age‐standardized and age‐, sex‐, and location‐specific estimates were generated. Leveraging the robust epidemiological modeling capabilities of the GBD framework, along with inequality metrics, including the slope index of inequality (SII) and the concentration index of inequality (CII), we uncovered pronounced disparities not only across countries and regions but also within them. Our findings underscore that aggregated regional data could mask potentially substantial cross‐national disparities and national aggregates could similarly obscure subnational and local differences. This has profound implications for understanding the distribution of long COVID risk, improving pandemic preparedness, and guiding equitable public health policy. Ultimately, this study provides an unprecedented evidence base to inform global‐to‐local health system strengthening and support data‐driven equity‐focused responses to future public health emergencies.

Background: Long noncoding RNAs (lncRNAs) regulate various essential biological processes, including cell proliferation, differentiation, apoptosis, migration, and invasion. However, in nasopharyngeal carcinoma (NPC), the clinical significance and mechanisms of lncRNAs in malignant progression are unknown. Methods: RNA sequencing and bioinformatic analysis were used to determine the potential function of RRFERV (radiation-resistant but ferroptosis-vulnerable), and its biological effects were investigated using in vitro and in vivo experiments. Western blotting, quantitative real-time reverse transcription PCR, RNA immunoprecipitation (RIP) assays, and flow cytometry detected RRFERV expression. Ferroptosis and lipid peroxidation were added to evaluate the relationship between it and radiotherapy resistance. Results: LncRNA–RRFERV was both highly expressed in NPC tissues and radiation-resistant cells. RRFERV is associated with poor clinical outcomes of NPC patients and stabilizes TEAD1 by competitive binding with microRNA-615-5p and microRNA-1293. RRFERV–TEAD1 signaling axis leads to malignant progression and radiotherapy resistance of NPC. Furthermore, we observed that NPC radiotherapy-resistance cells exist in a fragile oxidative stress equilibrium, which makes them more sensitive to ferroptosis inducers. Surprisingly, we found that RRFERV–TEAD1 signaling axis also plays a key role in mediating the lipid peroxidation levels of NPC radiotherapy-resistance cells through transcriptional activation of ACSL4/TFRC. Conclusions: RRFERV serves as an independent prognostic factor in NPC. During the malignant progression of NPC caused by high expression of RRFERV, ferroptosis can be induced to effectively kill cancer cells and reverse the radiotherapy resistance of NPC cells, suggesting a potential treatment approach for recurrent and refractory NPC.