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Background <p>Severe acute pancreatitis (SAP) is a critical gastrointestinal disorder associated with high mortality. Dysregulated ferroptosis, an iron-dependent form of cell death, is recognized as a pivotal mechanism driving SAP progression. Although Homoplantaginin (Homo) exhibits notable anti-inflammatory and antioxidant properties, its specific role in modulating ferroptosis during SAP remains unclear.</p> Objective <p>To investigate whether Homo alleviates SAP by inhibiting ferroptosis via the circDNMT3B/miR-20b-5p/SLC7A11 axis.</p> Methods <p>C57BL/6 mice (<i>n</i> = 10 per group) were randomly allocated into nine groups, including normal control, SAP model, and various intervention groups involving Homo treatment, circDNMT3B knockdown, and miR-20b-5p inhibition. SAP was induced via caerulein and LPS injections. Assessments included histopathological evaluation, serum analysis (amylase, cytokines IL-1β, IL-6, IL-18), measurement of ferroptosis markers (MDA, GSH, tissue iron), Western blotting for ferroptosis-related proteins (ACSL4, COX-2, SLC7A11, GPX4), and qRT-PCR for gene expression. The targeting relationship between miR-20b-5p and SLC7A11 was validated by dual-luciferase reporter assay.</p> Results <p>SAP mice demonstrated severe pancreatic injury and hallmarks of ferroptosis, including elevated inflammation, iron accumulation, increased ACSL4/COX-2 expression, and upregulation of miR-20b-5p, alongside suppressed SLC7A11 and GPX4. Homo treatment significantly mitigated pancreatic damage and reversed these ferroptosis-related changes. CircDNMT3B knockdown exacerbated SAP severity and attenuated the protective effect of Homo, indicating its dependence on circDNMT3B. Furthermore, the detrimental effects of circDNMT3B knockdown were partially rescued by concurrent inhibition of miR-20b-5p, suggesting that miR-20b-5p acts downstream of circDNMT3B within the protective pathway mediated by Homo. The dual-luciferase assay confirmed miR-20b-5p directly targets SLC7A11.</p> Conclusion <p>Our study demonstrates that Homo protects against SAP primarily by suppressing ferroptosis. Mechanistically, Homo upregulates circDNMT3B, which sequesters miR-20b-5p, thereby relieving its repression of SLC7A11, which in turn supports the GPX4-mediated antioxidant defense. These findings elucidate a novel molecular pathway in SAP-associated ferroptosis and highlight the circDNMT3B/miR-20b-5p/SLC7A11 axis as a promising therapeutic target.</p>

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Homoplantaginin protects pancreatic tissue in severe acute pancreatitis mice via inhibiting ferroptosis by modulating the circDNMT3B/miR-20b-5p/SLC7A11 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Xiao Teng,
  • Shanfeng Sheng,
  • Mingyuan Pan,
  • Yuyang Li,
  • Zheng Li

摘要

Background

Severe acute pancreatitis (SAP) is a critical gastrointestinal disorder associated with high mortality. Dysregulated ferroptosis, an iron-dependent form of cell death, is recognized as a pivotal mechanism driving SAP progression. Although Homoplantaginin (Homo) exhibits notable anti-inflammatory and antioxidant properties, its specific role in modulating ferroptosis during SAP remains unclear.

Objective

To investigate whether Homo alleviates SAP by inhibiting ferroptosis via the circDNMT3B/miR-20b-5p/SLC7A11 axis.

Methods

C57BL/6 mice (n = 10 per group) were randomly allocated into nine groups, including normal control, SAP model, and various intervention groups involving Homo treatment, circDNMT3B knockdown, and miR-20b-5p inhibition. SAP was induced via caerulein and LPS injections. Assessments included histopathological evaluation, serum analysis (amylase, cytokines IL-1β, IL-6, IL-18), measurement of ferroptosis markers (MDA, GSH, tissue iron), Western blotting for ferroptosis-related proteins (ACSL4, COX-2, SLC7A11, GPX4), and qRT-PCR for gene expression. The targeting relationship between miR-20b-5p and SLC7A11 was validated by dual-luciferase reporter assay.

Results

SAP mice demonstrated severe pancreatic injury and hallmarks of ferroptosis, including elevated inflammation, iron accumulation, increased ACSL4/COX-2 expression, and upregulation of miR-20b-5p, alongside suppressed SLC7A11 and GPX4. Homo treatment significantly mitigated pancreatic damage and reversed these ferroptosis-related changes. CircDNMT3B knockdown exacerbated SAP severity and attenuated the protective effect of Homo, indicating its dependence on circDNMT3B. Furthermore, the detrimental effects of circDNMT3B knockdown were partially rescued by concurrent inhibition of miR-20b-5p, suggesting that miR-20b-5p acts downstream of circDNMT3B within the protective pathway mediated by Homo. The dual-luciferase assay confirmed miR-20b-5p directly targets SLC7A11.

Conclusion

Our study demonstrates that Homo protects against SAP primarily by suppressing ferroptosis. Mechanistically, Homo upregulates circDNMT3B, which sequesters miR-20b-5p, thereby relieving its repression of SLC7A11, which in turn supports the GPX4-mediated antioxidant defense. These findings elucidate a novel molecular pathway in SAP-associated ferroptosis and highlight the circDNMT3B/miR-20b-5p/SLC7A11 axis as a promising therapeutic target.