Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.

Circadian rhythms are intrinsic timekeeping systems that orchestrate the physiological processes of living organisms in alignment with the 24-hour day-night cycle. These rhythms, governed by molecular clocks observed in almost every cell, regulate essential biological functions, including metabolism, hormone release, and sleep-wake cycles. Disruptions to these finely adjusted systems-due to modern lifestyle, shift work, or excessive exposure to artificial light-can misalign the internal clock with environmental cues. This misalignment has been increasingly associated with a spectrum of diseases, from cardiovascular disorders and metabolic syndrome to neuropsychiatric and oncological conditions (de Assis LVM and Kramer A. Genes Dev. 2024 Nov 27;38(21-24):933-951. doi: 10.1101/gad.352180.124). Understanding circadian rhythms provides an unique opportunity to explore their role as predictive and therapeutic tools for improving human health.Cardiometabolic health, a term covering the interconnected states of cardiovascular and metabolic health, serves as a critical determinant of overall well-being. Cardiometabolic diseases, including diabetes, hypertension, atherosclerosis, and related heart failure, have reached epidemic proportions globally, driven by sedentary behaviours, unhealthy diet, and environmental stressors. The circadian field offers a promising lens to explore the complex aetiology of these diseases (Gentile F, et al., Heart Fail Rev. 2024 Oct 11. doi: 10.1007/s10741-024-10447-1). Evidence suggests that disruptions in circadian rhythms can impair metabolic and cardiovascular function, highlighting their potential role in disease prediction and prevention. Moreover, circadian biology paves the way for advancements in personalized medicine, offering strategies to tailor interventions such as pharmacotherapy and lifestyle modifications to align with an individual's chronotype, enhancing therapeutic efficacy.Harnessing the circadian clock to develop preventive strategies for cardiovascular and metabolic diseases represents a paradigm shift in public health and clinical practice. Regular physical activity, timed to align with the body's natural rhythms, has been shown to significantly improve metabolic outcomes and cardiovascular resilience. Similarly, structured meal timing, such as time-restricted eating, optimizes metabolic efficiency by synchronizing nutrient intake with the body's circadian-driven processes. Maintaining consistent sleep-wake cycles and minimizing exposure to light during nighttime have been shown to regulate hormonal balance, reducing the risk of cardiometabolic disturbances. Additionally, pharmacological targeting of the circadian clock presents a promising strategy for restoring rhythmic balance and enhancing health outcomes. These preventive mechanisms emphasize the potential of circadian rhythm alignment as a noninvasive, cost-effective approach to improve population health. This Research Topic, Chronobiology in Cardiometabolic Health and Disease, brings together diverse perspectives on the profound correlation between circadian rhythms and cardiometabolic health. Disruptions to the body's internal clock are increasingly recognized as pivotal contributors to the development of cardiovascular and metabolic disorders, and this collection of studies highlights promising avenues for intervention and understanding.One focal area is the influence of exercise on circadian rhythms, showcasing its role as a non-photic zeitgeber. Shen and colleagues reviewed the effects of exercise on regulation of internal clock, which could act as a non-drug intervention for circadian rhythm disorders, with implications for improving cardiometabolic outcomes and overall health (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1282357/full).Another theme, discussed by Chen and colleagues, is the intricate dialogue between mitochondria and the endoplasmic reticulum, uncovering their role in cellular processes such as calcium signalling, lipid transport, and autophagy. Dysregulation of these pathways is linked to aging-related cardiovascular diseases, and targeting these interactions offers a novel therapeutic approach to mitigate the effects of aging on the cardiovascular system (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1389202/ full).Ma and colleagues provided further insights into the overlapping roles of endoplasmic reticulum stress and autophagy in aging and cardiovascular diseases. This research highlights potential strategies to counteract aging-associated pathologies and protect cardiovascular health by elucidating the molecular pathways underlying these processes (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1413853/ full).The collection also delves into the impact of time-restricted eating (TRE) as a promising dietary intervention. By aligning food intake with the body's circadian rhythms, TRE has shown potential to enhance metabolic balance, particularly in individuals with obesity and metabolic disorders. A review by Ribas-Latre and colleagues emphasizes the interaction between TRE, the circadian clock, and the gut microbiota, shedding light on how these factors collectively influence cardiometabolic health. Also, evidence suggests that TRE enhances insulin sensitivity and lowers inflammatory markers, mitigating metabolic disturbances. Aligning TRE with individual chronotypes may further optimize its cardiometabolic benefits (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1428601/ full).Lastly, Özata and colleagues provided genetic insights into circadian regulation through CLOCK gene polymorphisms. This work examines how genetic variations impact circadian behaviour, dietary patterns, and metabolic health, underscoring the importance of personalized approaches to nutrition and lifestyle interventions. The results suggest that CLOCK...

This review comprehensively explores the complex interplay between extracellular vesicles (ECVs)/exosomes and circadian rhythms, with a focus on the role of this interaction in hepatocellular carcinoma (HCC). Exosomes are nanovesicles derived from cells that facilitate intercellular communication by transporting bioactive molecules such as proteins, lipids, and RNA/DNA species. ECVs are implicated in a range of diseases, where they play crucial roles in signaling between cells and their surrounding environment. In the setting of cancer, ECVs are known to influence cancer initiation and progression. The scope of this review extends to all cancer types, synthesizing existing knowledge on the various roles of ECVs. A unique aspect of this review is the emphasis on the circadian-controlled release and composition of exosomes, highlighting their potential as biomarkers for early cancer detection and monitoring metastasis. We also discuss how circadian rhythms affect multiple cancer-related pathways, proposing that disruptions in the circadian clock can alter tumor development and treatment response. Additionally, this review delves into the influence of circadian clock components on ECV biogenesis and their impact on reshaping the tumor microenvironment, a key component driving HCC progression. Finally, we address the potential clinical applications of ECVs, particularly their use as diagnostic tools and drug delivery vehicles, while considering the challenges associated with clinical implementation.

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.

Background/Objectives: Chronic rhinosinusitis (CRS) is commonly accompanied by sleep disturbance and cognitive complaints, but the relationships among CRS, cognition, subjective sleep, and circulating inflammatory cytokines remain incompletely understood. Methods: In this case–control study, 80 adults with CRS and 98 controls completed validated sleep and sinonasal questionnaires and a 12-test cognitive battery assessing six domains. Plasma cytokines were measured in 101 participants with available biospecimens. Multivariable linear regression and exploratory correlation analyses were performed with false discovery rate correction. Results: Adjusted cognitive domain scores did not differ between CRS and controls. In age-by-group interaction models, CRS showed a nominally steeper age-associated decrease in episodic memory (β = −0.12, 95% CI −0.21 to −0.03; p = 0.009; q = 0.053), with weaker nominal patterns for working memory (β = −0.10, 95% CI −0.20 to −0.003; p = 0.044; q = 0.096) and visuospatial ability (β = −0.08, 95% CI −0.15 to −0.001; p = 0.048; q = 0.096). Plasma IL-6 was nominally higher in CRS after adjustment (β = 0.36, 95% CI 0.04 to 0.67; p = 0.026; q = 0.18) but did not remain significant after cytokine-level correction. Within CRS, exploratory analyses showed nominal inverse correlations between IL-6 and visuospatial ability (ρ = −0.36; p = 0.008; q = 0.236), as well as a nominal positive correlation between IL-13 and semantic memory (ρ = 0.33; p = 0.020; q = 0.236); however, none survived correction for multiple comparisons. Conclusions: Adults with CRS reported greater sleep-related burden and showed a nominally steeper age-related decrease in episodic memory. IL-6 and IL-13 showed nominal cognitive associations that did not survive correction, supporting the need for larger longitudinal studies to clarify clinical relevance.