Article Impact Level: HIGH Data Quality: STRONG Summary of Trends in Endocrinology & Metabolism, S1043276025001481. https://doi.org/10.1016/j.tem.2025.07.002 Dr. Dishu Zhou et al.
Points
- Circadian rhythm disruption from modern lifestyles triggers cellular stress responses that contribute to the development of many common digestive diseases.
- Beyond core clock genes, noncanonical clock regulators play a crucial role in maintaining 24-hour rhythmic processes, particularly when the primary biological clock is under stress.
- These alternative regulators ensure that essential daily cycles in digestive organs remain synchronized even when the main timekeeping genes are experimentally deactivated or disrupted.
- Understanding these noncanonical pathways offers promising new targets for drug development and expands the potential applications of chronopharmacology in treating gastrointestinal conditions.
- Chronotherapy, which includes the strategic timing of meals and medications, is a cost-effective and straightforward approach to align with the body’s natural rhythms.
Summary
This comprehensive review synthesizes emerging research on the pathophysiology of circadian disruption in the digestive system, with a focus on the role of noncanonical clock regulators in mediating cellular stress responses. Modern lifestyle factors, including shift work and irregular meal patterns, are identified as significant disruptors of the 24-h rhythms governing digestive gene expression and physiological processes, contributing to conditions like non-alcoholic fatty liver disease and inflammatory bowel disease. The paper posits that, in addition to the core clock components (e.g., BMAL1/CLOCK), a network of noncanonical regulators provides a resilient, secondary timekeeping mechanism crucial for maintaining cellular homeostasis, particularly under conditions of metabolic or environmental stress.
The authors collate findings from studies where deactivating core clock genes did not abolish the 24-hour cycles of most rhythmic genes, indicating these noncanonical factors are essential for connecting the body’s timing system to diverse stress response pathways. These regulators are shown to integrate signals from stressors such as high-fat diets, altered feeding times, exercise, and aging to reshape rhythmic gene and metabolic patterns. This model proposes that these noncanonical regulators function as critical nodes linking circadian biology to the cellular stress response apparatus, thereby representing a new class of potential therapeutic targets for digestive disorders.
The clinical implications center on chronotherapy, encompassing both chrononutrition and chronopharmacology, as a cost-effective strategy to mitigate circadian-driven stress on the digestive system. By understanding the organ-specific activity of noncanonical regulators, targeted therapies can be developed. The authors advocate for a future of personalized medicine where real-time monitoring of an individual’s internal clock could guide tailored nutritional and pharmacological interventions. This approach aims to align treatment schedules with endogenous rhythms to optimize therapeutic efficacy and improve overall digestive health and well-being.
Link to the article: https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(25)00148-1
References Zhou, D., López-Valiente, R. E., Mattar, S. G., & Guan, D. (2025). Noncanonical clock regulators control stress responses in digestive diseases. Trends in Endocrinology & Metabolism, S1043276025001481. https://doi.org/10.1016/j.tem.2025.07.002
