2. Academic Validation
  3. Mechanistic insights into the role of FAT10 in modulating NCOA4-mediated ferroptosis in pancreatic acinar cells during acute pancreatitis

Mechanistic insights into the role of FAT10 in modulating NCOA4-mediated ferroptosis in pancreatic acinar cells during acute pancreatitis

  • Cell Death Dis. 2025 May 15;16(1):385. doi: 10.1038/s41419-025-07715-9.
Lingpeng Liu 1 2 3 4,  Ben Che 1 2 3 4,  Wenming Zhang 1 2 3 4,  Dongnian Du 1 2 3 4,  Dandan Zhang 1 2 3 4,  Jiajuan Li 1 2 3 4,  Zehao Chen 1 2 3 4,  Xuzhe Yu 1 2 3 4,  Miao Ye 1 2 3 4,  Wei Wang 1 2 3 4,  Zijing Li 1 2 3 4,  Fei Xie 1 2 3 4,  Qing Wang 1 2 3 4,  Leifeng Chen 5 6 7,  Jianghua Shao 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 2 Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 3 Liver Cancer Institute, Nanchang University, Nanchang, China.
  • 4 Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 5 Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. 18770099029@126.com.
  • 6 Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. 18770099029@126.com.
  • 7 Precision Oncology Medicine Center, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China. 18770099029@126.com.
  • 8 Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. shao5022@163.com.
  • 9 Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China. shao5022@163.com.
  • 10 Liver Cancer Institute, Nanchang University, Nanchang, China. shao5022@163.com.
  • 11 Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. shao5022@163.com.
  • 12 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Nanchang University, Nanchang, China. shao5022@163.com.
PMID: 40374601 DOI: 10.1038/s41419-025-07715-9
Abstract

Acute pancreatitis (AP) is characterised by inflammation and cell death in pancreatic tissue, with Ferroptosis playing a critical role in its pathophysiology by mediating cellular damage and exacerbating inflammation. This study investigated the role of human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10) in AP, specifically its involvement in Ferroptosis within pancreatic acinar cells. We observed that FAT10 expression was significantly elevated in AP tissues, which correlated with increased Ferroptosis. Overexpression of FAT10 in pancreatic acinar cells enhances Ferroptosis, whereas its knockdown reduced levels of Ferroptosis markers. Furthermore, we confirmed that FAT10 enhanced Ferroptosis in pancreatic acinar cells primarily by upregulating nuclear receptor coactivator 4 (NCOA4) expression. Mechanistic investigations revealed that FAT10 regulates NCOA4 expression to promote Ferroptosis in a complex manner. FAT10 inhibits NCOA4 ubiquitination by reducing ubiquitin-NCOA4 complexes. Meanwhile, NCOA4 expression increased alongside the increase in FAT10-NCOA4 complexes, which are resistant to proteasomal degradation. Notably, we identified silibinin, a natural compound, as an effective inhibitor of the FAT10-NCOA4 axis, leading to reduced Ferroptosis and alleviation of pancreatic damage in vivo. Silibinin treatment decreased the levels of ferroptosis-related proteins and inflammatory markers in both cell and animal models. Our findings highlight the FAT10-NCOA4 axis as a crucial regulator of Ferroptosis in pancreatic acinar cells and suggest that targeting this pathway could offer a therapeutic strategy for mitigating AP. This study provides new insights into the regulatory mechanisms of Ferroptosis in pancreatic acinar cells, identifying FAT10 as a potential therapeutic target for AP management.

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