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

作者：Qian Yu, Hui Song, Xiaoya Shi, Liang Zhu, Yu Liang, Ruining Gong, Xiaowu Dong, Shanglong Liu, Hai-zhen Wang, Ying-luo Wang, Jiu-fa Cui, Xin Yang, Y Q Chen, Ce Gao, Zhan Yang, Zhu Qing-tian, Chang Li, Huan Zhang, Jieer Ying, Meifang Zheng, Yantao Tian, Hai-tao Hu, Xin-xin Shao, Yue Li, Mingguang Mo, Yun Lu, Zheng Ma, Shun-li Fu, Qing-hui Niu, Yuan-yu Liao, Chenyang Zhao, Xin Liu, Ashok Kumar Saluja, Jigang Wang, Xiao-yu Li, Song-Yue Guo, Wei-hua Wang, S Wang, Bin Liu, Guo-tao Lu, He Ren · 发表于：Signal Transduction and Targeted Therapy · 年份：2026 · DOI：10.1038/s41392-025-02562-8 · 被引用次数：16 · 研究领域：Macrophage Migration Inhibitory Factor、Liver Disease Diagnosis and Treatment、Biochemical Acid Research Studies

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...