The RASSF1C-HIF-1α axis drives macrophage lipid metabolism to promote pancreatic cancer

作者：Ting Zhan, Min Huang, Mengge Chen, W X Chen, Yiyun Wang, Xiaoli Chen, Yanli Zou, Meng Liu, Qingxi Zhu, Xia Tian, Zheng Han, Xiaodong Huang · 发表于：Cell Death and Disease · 年份：2026 · DOI：10.1038/s41419-026-08609-0 · 研究领域：Cancer, Hypoxia, and Metabolism、Ferroptosis and cancer prognosis、Immune cells in cancer

Pancreatic adenocarcinoma (PAAD) has a poor prognosis. Its microenvironment is closely associated with tumor progression and immune evasion. This study combines single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to reveal the critical role of tumor-associated macrophages (TAMs) in PAAD. Ras association domain family member 1 C (RASSF1C) is significantly upregulated under hypoxia, enhancing glycolysis by promoting the Warburg effect. This generates lactate and contributes to acidification of the tumor microenvironment (TME). Lactate activates TAMs and reprograms their lipid metabolism, promoting PAAD migration and invasion. Further investigation demonstrated that lactate suppressed ubiquitin-fold modifier 1 ligating enzyme 1 (UFL1) protein levels in macrophages, thereby weakening the protective effect of UFL1-mediated interferon regulatory factor 7 (IRF7) UFMylation. This suppression led to enhanced K48-linked ubiquitination of IRF7 and accelerated proteasomal degradation, ultimately reducing IRF7 stability and impairing lipid metabolic functions in macrophages. Additional mechanistic evidence showed that UFL1-UFMylation axis maintains IRF7 homeostasis by counteracting K48-linked ubiquitin-mediated degradation. Moreover, immunohistochemical (IHC) validation using tissue microarrays from 20 human pancreatic ductal adenocarcinoma (PDAC) specimens revealed that the overall expression of RASSF1C and hypoxia-inducible factor-1 alpha (HIF-1α) was higher than tha...