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The RASSF1C-HIF-1α axis drives macrophage lipid metabolism to promote pancreatic cancer
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  • Published: 30 March 2026

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

  • Ting Zhan1 na1,
  • Min Huang1 na1,
  • Mengge Chen1,2 na1,
  • Wei Chen1,
  • Yiyun Wang1,
  • Xiaoli Chen1,
  • Yanli Zou1,
  • Meng Liu1,
  • Qingxi Zhu1,
  • Xia Tian1,
  • Zheng Han1 &
  • …
  • Xiaodong Huang1 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer metabolism
  • Post-translational modifications

Abstract

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 that of UFL1 and IRF7. RASSF1C expression was significantly positively correlated with HIF-1α and negatively correlated with UFL1 and IRF7. Clinicopathological correlation analysis further showed that high RASSF1C expression was associated with poor differentiation and advanced TNM stage, whereas low UFL1 and IRF7 expression was associated with lymph node metastasis. Collectively, this study demonstrated that the hypoxia-RASSF1C-HIF-1α axis reshaped TAM function through lactate-mediated immunometabolic regulation and promoted PAAD progression by inhibiting UFL1-mediated IRF7 UFMylation, thereby reducing IRF7 stability. These findings identify potential therapeutic targets for combined metabolic and immune interventions in PAAD.

Graphic abstract. Schematic illustration of the molecular mechanism by which the RASSF1C-HIF-1α axis induces glycolytic reprogramming, drives lactate accumulation in the acidic TME, and promotes lactate flux into macrophages, thereby facilitating UFL1-IRF7 interaction and ultimately accelerating PAAD progression.

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Data availability

All data can be provided as needed.

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Funding

This work was supported by a grant from the Natural Science Foundation of Hubei Province in China 2025AFB974 (TZ), the Health Commission of Hubei Province scientific research project WJ2023M129 (WC).

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  1. These authors contributed equally: Ting Zhan, Min Huang, Mengge Chen.

Authors and Affiliations

  1. Department of Gastroenterology, Tongren hospital of WuHan University(WuHan Third Hospital), Wuhan, China

    Ting Zhan, Min Huang, Mengge Chen, Wei Chen, Yiyun Wang, Xiaoli Chen, Yanli Zou, Meng Liu, Qingxi Zhu, Xia Tian, Zheng Han & Xiaodong Huang

  2. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Mengge Chen

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Contributions

T.Z., M.L., X.T., Z.H., and X.H. conceived and designed the study. M.C., Q.Z., T.Z., M.H., X.C., M.L., and Y.Z. performed the experiments. T.Z., Z.H., Y.W., M.C., X.H., and X.T. analyzed the data. T.Z., M.C., M.H., X.T., Q.Z., and X.H. wrote the manuscript. wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Qingxi Zhu, Xia Tian, Zheng Han or Xiaodong Huang.

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Zhan, T., Huang, M., Chen, M. et al. The RASSF1C-HIF-1α axis drives macrophage lipid metabolism to promote pancreatic cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08609-0

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  • Received: 29 September 2025

  • Revised: 16 February 2026

  • Accepted: 09 March 2026

  • Published: 30 March 2026

  • DOI: https://doi.org/10.1038/s41419-026-08609-0

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