Citations

Background Disruption in rest‐activity rhythm (RAR) is an emerging risk factor for cardiovascular disease (CVD) and mortality, but the strength of evidence is unclear. Therefore, we conducted a systematic review and meta‐analysis to assess associations between RAR characteristics and cardiovascular disease incidence or prevalence, cardiovascular mortality, and all‐cause mortality. Methods A systematic search was conducted in PubMed, Web of Science, Cochrane Library, and Embase for cohort or cross‐sectional studies published up to August 2025. The exposure variables were nonparametric RAR parameters, including interdaily stability (describing day‐to‐day stability of the RAR), intradaily variability (a measure of RAR fragmentation), and relative amplitude (indicating robustness or strength of the RAR). The primary outcomes were cardiovascular mortality and all‐cause mortality. The secondary outcomes included cardiovascular disease prevalence and incidence. Results Seven studies involving 109 365 participants were included. Pooled results showed that higher intradaily variability was associated with a significantly increased risk of all‐cause mortality (hazard ratio [HR], 1.05 [95% CI, 1.02–1.09]) and cardiovascular disease prevalence (odds ratio, 1.73 [95% CI, 1.21–2.47]). Lower relative amplitude was significantly associated with higher cardiovascular mortality (HR, 1.50 [95% CI, 1.13–1.98]) and all‐cause mortality (HR, 1.46 [95% CI, 1.27–1.68]). Interdaily stability showed no significant associations with any outcome. Conclusions Measures of disrupted rest‐activity rhythms were associated with increased cardiovascular mortality, and all‐cause mortality. These findings support using RAR metrics as early, noninvasive risk indicators. Future work should investigate whether appropriately timed physical activity and sleep, as well as other interventions targeting RAR can mitigate cardiovascular risk.

Abstract The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element–driven luciferase-based screen against US Food and Drug Administration–approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.