Endocrine-exocrine miR-503-322 drives aging-associated pancreatitis via targeting MKNK1 in acinar cells

Kerong Liu, Tingting Lv, Lu He, Wei Tang, Yan Zhang, Xiao Xiao, Yating Li, Xiaoai Chang, Shusen Wang, Stephen J. Pandol (), Ling Li (), Xiao Han () and Yunxia Zhu ()
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Kerong Liu: Nanjing Medical University
Tingting Lv: Nanjing Medical University
Lu He: Nanjing Medical University
Wei Tang: Geriatric Hospital of Nanjing Medical University
Yan Zhang: Children’s Hospital of Nanjing Medical University
Xiao Xiao: Nanjing Medical University
Yating Li: Nanjing Medical University
Xiaoai Chang: Nanjing Medical University
Shusen Wang: Nankai University
Stephen J. Pandol: Cedars-Sinai Medical Center
Ling Li: Southeast University
Xiao Han: Nanjing Medical University
Yunxia Zhu: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Aging is the risk factor for chronic pancreatitis and severity determinant for its acute attack, yet the underlying cause is unclear. Here, we demonstrate that senescent β-cells of endocrine pancreas decide the onset and severity of chronic and acute pancreatitis. During physiological aging, senescent β-cells increase the expression of miR-503-322 which is secreted as small extracellular vesicles to enter exocrine acinar cells, driving a causal and reversible role on aging-associated pancreatitis. Mechanistically, miR-503-322 targets MKNK1 to inhibit acinar-cell secretion leading to autodigestion and repress proliferation causing repair damage of exocrine pancreas. In the elderly population, serum miR-503 concentration is negatively correlated with amylase, prone to chronic pancreatitis due to increased miR-503 and decreased MKNK1 in the elderly pancreas. Our findings highlight the miR-503-322–MKNK1 axis mediating the endocrine-exocrine regulatory pathway specifically in aged mice and humans. Modulating this axis may provide potential preventive and therapeutic strategies for aging-associated pancreatitis.

Date: 2025
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DOI: 10.1038/s41467-025-57615-x

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