LAUSR

Chronic pancreatitis (CP) is characterized by progressive fibrosis and exocrine dysregulation, which have long been considered irreversible. As a peripheral oscillator, the pancreas harbors autonomous and self-sustained timekeeping systems in both its endocrine and exocrine compartments, although the role of the latter remains poorly understood. By using different models of CP established in mice with dysfunctional pancreatic clocks, we found that the local clock played an important role in CP pathology, and genetic or external disruption of the pancreatic clock exacerbated fibrogenesis and exocrine insufficiency. Mechanistically, an impaired retinoic acid receptor–related orphan receptor A (Rora)/nuclear receptor subfamily 1, group D, member 1 (Nr1d1)/aryl hydrocarbon receptor nuclear translocator-like (Arntl or Bmal1) loop, called the circadian stabilizing loop, resulted in the deficiency of pancreatic Bmal1, which was responsible for controlling the fibrogenic properties of pancreatic stellate cells (PSCs) and for rewiring the function of acinar cells in a clock–TGF signaling–IL-11/IL-11RA axis–dependent manner. During PSC activation, the antagonistic interaction between Nr1d1 and Rora was unbalanced in response to the loss of cytoplasmic retinoid-containing lipid droplets. Patients with CP also exhibited reduced production of endogenous melatonin. Enhancing the clock through pharmacological restoration of the circadian stabilizing loop using a combination of melatonin and the Rora agonist SR1078 attenuated intrapancreatic pathological changes in mouse models of CP. Collectively, this study identified a protective role of the pancreatic clock against pancreatic fibrosis and exocrine dysfunction. Pancreatic clock–targeted therapy may represent a potential strategy to treat CP. Description Disruption of the pancreatic clock promotes chronic pancreatitis, and restoration of the clock stabilizing loop shows therapeutic potential in mice. Restarting the (pancreatic) clock The pancreas has an autonomous circadian clock, but the effects of the clock on chronic pancreatitis (CP) are not well understood. Here, using human tissues and transgenic mouse models, Jiang and colleagues found that disruption of the pancreatic clock in CP led to worsened fibrogenesis and exocrine insufficiency. They identified a circadian stabilizing loop that, when impaired, resulted in loss of pancreatic Bmal1, which led to pancreatic stellate cell activation and fibrogenesis. The combination of melatonin and the retinoic acid receptor–related orphan receptor A agonist SR1078 attenuated fibrotic changes in mouse models of CP, suggesting that therapies targeting the pancreatic clock could be further investigated as a strategy to treat CP in humans.