CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.

Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts in vitro and in vivo. Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.

Increased risk of dementia among people with a history of fractures: a systematic review and meta-analysis of population-based studies.

Background: Emerging evidence suggests that there may be an association between a history of fractures and dementia risk, but the epidemiological findings are inconsistent. We, therefore, conducted a meta-analysis to systematically assess the risk of dementia among people with a history of fractures. Methods: We comprehensively searched four electronic databases (PubMed, Web of Science, Embase, and Cochrane Library) for relevant literature published from inception to 10 January 2023. Longitudinal observational studies that investigated the association between any type of fracture occurrence and the subsequent risk of dementia were included for qualitative and quantitative analysis. Risk estimates were pooled using fixed-effects or random-effects models according to the level of heterogeneity. The Newcastle-Ottawa scale was used to evaluate the risk of bias in the included studies. Results: A total of seven population-based studies involving 3,658,108 participants (136,179 with a history of fractures) were eventually included. Pooled results showed a significant association between fracture and subsequent risk of dementia [hazard ratio (HR) = 1.28, 95% confidence interval (CI): 1.11-1.48] in cohort studies. Patients with fractures at different sites showed a similar trend toward increased risk of subsequent dementia. No gender, age, region, duration of follow-up, study quality, or study design specificity were observed. Sensitivity analysis indicates that the current results are robust. No publication bias existed. The results were similar in the cohort study with the standardized incidence ratio (SIR) as the statistical measure (SIR = 1.58, 95% CI: 1.25-2.00) and in the case-control study (OR = 1.38, 95% CI: 1.18-1.61). Of note, the causal relationship between fracture and dementia was not demonstrated in this meta-analysis. Conclusion: People with a history of fractures are at increased risk of developing dementia. Enhanced screening and preventive management of dementia in people with a history of fractures may be beneficial.