Endocrine-exocrine miR-503-322 drives aging-associated pancreatitis via targeting MKNK1 in acinar cells
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.
Authors
- Lu He (ORCID: https://orcid.org/0000-0003-2749-7857)
- Kerong Liu (ORCID: https://orcid.org/0009-0009-0588-0194)
- Yunxia Zhu (ORCID: https://orcid.org/0000-0002-4597-4445)
- Stephen J. Pandol (ORCID: https://orcid.org/0000-0003-0818-6017)
- Xiao Han (ORCID: https://orcid.org/0000-0002-6467-1802)
- Ling Li (ORCID: https://orcid.org/0000-0003-0083-6978)
- Xiao Xiao (ORCID: https://orcid.org/0000-0003-0682-9509)
- Yan Zhang (ORCID: https://orcid.org/0009-0005-7322-7809)
- Shusen Wang (ORCID: https://orcid.org/0000-0002-2323-6564)
- Wei Tang (ORCID: https://orcid.org/0009-0002-5704-7806)
- Yating Li (ORCID: https://orcid.org/0000-0002-2134-0595)
- Tingting Lv (ORCID: https://orcid.org/0000-0002-8976-3703)
- Xiaoai Chang
Institutions
- Jiangnan University (CN)
- Cedars-Sinai Medical Center (US)
- Nankai University (CN)
- Tianjin First Center Hospital (CN)
- Zhongda Hospital Southeast University (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Jiangsu Province Hospital (CN)
- Tianjin Medical University (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1038/s41467-025-57615-x
- Citations
- 3
- Primary Topic
- Pancreatitis Pathology and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 6.02
Funders
- National Natural Science Foundation of China
- Wuxi Municipal Bureau on Science and Technology