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

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  • Kerong Liu

    (Nanjing Medical University
    Wuxi Children’s Hospital)

  • 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
    The First Affiliated Hospital of Nanjing Medical University)

  • Yunxia Zhu

    (Nanjing Medical University)

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.

Suggested Citation

  • 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 & Yunxia Zhu, 2025. "Endocrine-exocrine miR-503-322 drives aging-associated pancreatitis via targeting MKNK1 in acinar cells," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57615-x
    DOI: 10.1038/s41467-025-57615-x
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