Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies

  • Cancers (Basel). 2025 May 31;17(11):1853. doi: 10.3390/cancers17111853.
Yahui Li  1 ,  Zachary Ladd  1  2 ,  Zhaohui Xiong  3 ,  Candice Bui-Linh  3 ,  Chorlada Paiboonrungruang  3 ,  Boopathi Subramaniyan  1 ,  Huan Li  1 ,  Haining Wang  4 ,  Curt Balch  3 ,  David D Shersher  1  2  5 ,  Francis Spitz  1  2  5 ,  Xiaoxin Chen  1  2  3  5
Affiliations
  • 1. Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA.
  • 2. Cooper Medical School of Rowan University, Camden, NJ 08103, USA.
  • 3. Coriell Institute for Medical Research, Camden, NJ 08103, USA.
  • 4. Insilico Medicine Canada Inc., Montreal, QC H3B 4W8, Canada.
  • 5. MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA.
PMID: 40507333 DOI: 10.3390/cancers17111853
Abstract

The lethality of esophageal squamous cell carcinoma (ESCC), and Other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the functional role of NRF2 and therapeutic strategies. Current data suggest that NRF2 hyperactivation (NRF2high) may promote lymphatic metastasis of ESCC by affecting the extracellular matrix (ECM), epithelial-mesenchymal transition (EMT), lymphangiogenesis, immune evasion, metabolic programming, and Hippo signaling. We also update the latest developments in NRF2 inhibitors, their mechanisms of action, screening strategies, and approaches for evaluating compound efficacy. Finally, we highlight the utility of animal models for mechanistic studies and therapeutic development. We believe elucidation of the functional role of NRF2 in ESCC lymphatic metastasis and developing proper NRF2 inhibitors will greatly improve the clinical prognosis of ESCC in human patients.

Keywords
NRF2; esophageal squamous cell carcinoma; lymphatic metastasis.
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