Journal Article

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

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

2026

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/322 / 631/67/580 / 692/4028/67/1504 / Adenocarcinoma / Animal models / Animals / Cancer Research / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - pathology / CD44 antigen / Cell Biology / Cell Line, Tumor / Comorbidity / Diabetes / Disease Progression / Fatty liver / Female / Hospitals / Humans / Hyaluronan Receptors - genetics / Hyaluronan Receptors - metabolism / Internal Medicine / Intramolecular Oxidoreductases - genetics / Leukocyte migration / Liver cancer / Liver diseases / Liver Neoplasms - genetics / Liver Neoplasms - pathology / Liver Neoplasms - secondary / Macrophage migration inhibitory factor / Macrophage Migration-Inhibitory Factors - genetics / Magnetic resonance imaging / Male / Malignancy / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Microenvironments / Middle Aged / Neoplasm Metastasis / Non-alcoholic Fatty Liver Disease - complications / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - pathology / Oncology / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Pathology / Therapeutic targets / Tumor Microenvironment - genetics