Serum Hsa-miR-4695-5p Serves as a Novel Diagnostic Biomarker for Acute Severe Pancreatitis and Exacerbates Pathological Injury by Targeting SESN2

Jiasui Chai; Jiejie Dong; Weixiao Hou; Jiayong Ning; Yan Liu; Yan Chen; Tong Zhang; Xingren Guo; Peng Yao

doi:10.1007/s10620-025-09186-6

Serum Hsa-miR-4695-5p Serves as a Novel Diagnostic Biomarker for Acute Severe Pancreatitis and Exacerbates Pathological Injury by Targeting SESN2

Dig Dis Sci. 2025 Jul 2. doi: 10.1007/s10620-025-09186-6. Online ahead of print.

Authors

Jiasui Chai¹, Jiejie Dong¹, Weixiao Hou¹, Jiayong Ning¹, Yan Liu¹, Yan Chen¹, Tong Zhang¹, Xingren Guo¹, Peng Yao²

Affiliations

¹ Department of Hepatobiliary Surgery, Yuncheng Central Hospital Affiliated to Shanxi Medical University, No. 3690, Hedong East Street, Yanhu District, Yuncheng, 044000, Shanxi Province, China.
² Department of Hepatobiliary Surgery, Yuncheng Central Hospital Affiliated to Shanxi Medical University, No. 3690, Hedong East Street, Yanhu District, Yuncheng, 044000, Shanxi Province, China. yaopengyc@stu.xhu.edu.cn.

PMID: 40601221
DOI: 10.1007/s10620-025-09186-6

Abstract

Objective: Increasing evidence has revealed that aberrantly expressed miRNAs play important roles in stimulating pathogenesis and maintaining disease progression. However, the potential miRNAs involved in acute pancreatitis (AP) are still unclear. The present study aimed to explore the clinical significance of hsa-miR-4695-5p and its role behind AP progression.

Method: Serum samples from 86 patients with AP (mild: 19 cases, moderate: 25 cases; severe: 42 cases) and 33 healthy cases were collected, and hsa-miR-4695-5p levels were detected by qRT-PCR analysis. Receiver operating characteristic (ROC) curves were employed to assess the diagnostic performance of hsa-miR-4695-5p. Caerulein-treated HPDE6-C7 cells were served as an in vitro cellular model for AP, cell viability, pro-inflammatory cytokines (TNF-α, IL-6 and IL-33) and oxidative stress were detected after silencing or overexpression of hsa-miR-4695-5p by CCK-8, ELISA, MDA and SOD kits. The influence of hsa-miR-4695-5p on macrophage polarization was verified through cell co-cultivation system by the detection of M1 and M2 macrophage markers. The targeting relationships between hsa-miR-4695-5p and sestrin 2 (SESN2) were confirmed by bioinformatics, luciferase reporter and RNA pull-down assays. In addition, a mouse AP model was used to confirm hsa-miR-4695-5p's role in AP.

Results: We found that hsa-miR-4695-5p was upregulated in patients with AP relative to normal cases, and higher hsa-miR-4695-5p expression was observed in severe AP cases relative to mild and moderate AP cases. The combination of hsa-miR-4695-5p and serum amylase showed better diagnostic efficacy for severe AP than hsa-miR-4695-5p alone (AUC of 0.964 and 0.847). Interfering hsa-miR-4695-5p improved cell viability and increased SOD activity in caerulein-treated HPDE6-C7 cells, decreased MDA, TNF-α, IL-6 and IL-33 levels, and reduced the macrophage polarization toward M1. Reinforcing hsa-miR-4695-5p caused the opposite effects. SESN2 levels were downregulated in patients with severe AP and caerulein-treated HPDE6-C7 cells, and SESN2 was a direct target of hsa-miR-4695-5p. Moreover, SESN2 knockdown reversed the effects of interfering hsa-miR-4695-5p in caerulein-treated HPDE6-C7 cells. In vivo injection of hsa-miR-4695-5p antagomir attenuated pathological injury in AP mice.

Conclusion: Upregulation of serum hsa-miR-4695-5p could be a novel biomarker for diagnosis of severe AP, and hsa-miR-4695-5p may promote pathological injury in severe AP via targeting SESN2 expression.

Keywords: AP; Has-miR-4695-5p; Oxidative stress; Pro-Inflammatory cytokines; SESN2.