bims-ciryme 2025-10-26 papers

Science. 2025 Oct 23. 390(6771): eadp3065

Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice.

Daniel C Levine, Rasmus H Reeh, Thomas McMahon, Thomas Mandrup-Poulsen, Ying-Hui Fu, Louis J Ptáček.

The circadian clock maintains synchrony between biological processes and light/dark cycles by integrating environmental cues. How the clock adapts to seasonal variations in the environment is incompletely understood. We found that a high-fat diet increased phosphorylation of the clock protein PERIOD2 (PER2) on serine 662 (S662), which was necessary and sufficient for regulating phase shifting of daily locomotor activity to entrain to seasonal light cycles. PER2-S662 phosphorylation correlated with genome-wide expression pathways that regulate polyunsaturated fatty acid (PUFA) conversion into oxylipins in the hypothalamus. Partial hydrogenation of dietary PUFAs increased hypothalamic PER2-S662 phosphorylation and entrainment to a summer photoperiod in control mice, but not in mice for which PER2-S662 could not be phosphorylated. PER2-S662 phosphorylation is influenced by, and alters the regulation of, unsaturated fat to control circadian phase shifting across the seasons.

DOI: https://doi.org/10.1126/science.adp3065

Cell Rep. 2025 Oct 20. pii: S2211-1247(25)01084-8. [Epub ahead of print]44(11): 116313

Targeting the hepatic circadian clock concomitant with tyrosine kinase inhibition reverses late-stage hepatocellular carcinoma.

Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase expression and related metabolite abundance and that P2-HNF4α regulates the carnitine palmitoyl transferase I gene. Finally, using different preclinical models, we show that the anti-tumor activity of TKIs, when they are co-administered with NOB, is maximal. Our results suggest that chronotherapy and combination therapy might provide improved clinical outcomes for individuals with BMAL1-deficient HCC.

Keywords: BMAL1; CP: Cancer; CP: Metabolism; CPT1A; HNF4α; acylcarnitine; chronotherapy; circadian; hepatocellular carcinoma; metabolism; nobiletin; tyrosine kinase inhibitors

DOI: https://doi.org/10.1016/j.celrep.2025.116313

JAMA Netw Open. 2025 Oct 01. 8(10): e2539031

Light Exposure at Night and Cardiovascular Disease Incidence.

Daniel P Windred, Angus C Burns, Martin K Rutter, Jacqueline M Lane, Richa Saxena, Frank A J L Scheer, Sean W Cain, Andrew J K Phillips.

Importance: Light at night causes circadian disruption, which is a known risk factor for adverse cardiovascular outcomes. However, it is not well understood of cardiovascular diseases.
Objective: To assess whether day and night light exposure is associated with incidence of cardiovascular diseases, and whether associations of light with cardiovascular diseases differ according to genetic susceptibility, sex, and age.
Design, Setting, and Participants: This prospective cohort study analyzed cardiovascular disease records across 9.5 years (June 2013 to November 2022) from UK Biobank participants who wore light sensors in a naturalistic setting. Data were analyzed from September 2024 to July 2025.
Exposure: Approximately 13 million hours of light exposure data, tracked by wrist-worn light sensors (1 week each), categorized into the 0 to 50th, 51st to 70th, 71st to 90th, and 91st to 100th percentiles.
Main Outcomes and Measures: Incidence of coronary artery disease, myocardial infarction, heart failure, atrial fibrillation, and stroke after light tracking were derived from UK National Health Service records. Risks of cardiovascular diseases were assessed using Cox proportional hazards models (3 primary models adjusted at 3 levels) and reported as hazard ratios (HRs).
Results: A total of 88 905 individuals were included (mean [SD] age, 62.4 [7.8] years; 50 577 female [56.9%]). Compared with individuals with dark nights (0-50th percentiles), those with the brightest nights (91st-100th percentiles) had significantly higher risks of developing coronary artery disease (adjusted HR [aHR], 1.32; 95% CI, 1.18-1.46), myocardial infarction (aHR, 1.47; 95% CI, 1.26-1.71), heart failure (aHR, 1.56; 95% CI, 1.34-1.81), atrial fibrillation (aHR, 1.32; 95% CI, 1.18-1.46), and stroke (aHR, 1.28; 95% CI, 1.06-1.55). These associations were robust after adjusting for established cardiovascular risk factors, including physical activity, smoking, alcohol, diet, sleep duration, socioeconomic status, and polygenic risk. Larger-magnitude associations of night light with risks of heart failure (P for interaction = .006) and coronary artery disease (P for interaction = .02) were observed for females, and larger-magnitude associations of night light with risks of heart failure (P for interaction = .04) and atrial fibrillation (P for interaction = .02) were observed for younger individuals in this cohort.
Conclusions and Relevance: In this cohort study, night light exposure was a significant risk factor for developing cardiovascular diseases among adults older than 40 years. These findings suggest that, in addition to current preventive measures, avoiding light at night may be a useful strategy for reducing risks of cardiovascular diseases.

DOI: https://doi.org/10.1001/jamanetworkopen.2025.39031