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<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P &lt; 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P &lt; 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.</p>

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Metabolic dysfunction-associated steatotic liver disease accelerates pancreatic cancer progression and metastasis via the macrophage migration inhibitory factor-CD44 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Qian Yu,
  • Hui Song,
  • Xiao-ya Shi,
  • Liang Zhu,
  • Yu Liang,
  • Rui-ning Gong,
  • Xiao-wu Dong,
  • Shang-long Liu,
  • Hai-zhen Wang,
  • Ying-luo Wang,
  • Jiu-fa Cui,
  • Xiao-nan Yang,
  • Ying Chen,
  • Chao Gao,
  • Zhan Yang,
  • Qing-tian Zhu,
  • Chang Li,
  • Huan Zhang,
  • Jie-er Ying,
  • Mei-fang Zheng,
  • Yan-tao Tian,
  • Hai-tao Hu,
  • Xin-xin Shao,
  • Yue Li,
  • Ming-guang Mo,
  • Yun Lu,
  • Zheng Ma,
  • Shun-li Fu,
  • Qing-hui Niu,
  • Yuan-yu Liao,
  • Chen-yang Zhao,
  • Xin Liu,
  • Ashok K. Saluja,
  • Ji-gang Wang,
  • Xiao-yu Li,
  • Song-yue Guo,
  • Wei-hua Wang,
  • Song Wang,
  • Bin Liu,
  • Guo-tao Lu,
  • He Ren

摘要

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.