NUPR1 as a central stress-adaptation node in cancer: integrating metabolic rewiring, cell death, and therapy resistance.

Tanqing Long, Qi Wang, Yinpeng Le, Mi Zhang, Yan Sun, Juan Iovanna, Lei Li, Chuanrui Xu, Juan Liu

Journal: Journal of biomedical science 2026;33(1):

PMID: 42104400

Abstract

Nuclear protein 1 (NUPR1) is an intrinsically disordered, stress-adaptive regulator that sits at the intersection of transcriptional plasticity and proteostatic control, broadly upregulated across malignancies and tightly associated with poor prognosis. Here, we synthesize evidence positioning NUPR1 as a central node of tumor adaptation that integrates metabolic rewiring, proteostatic balance, and cell-death checkpoints into a unified stress-response framework. NUPR1 orchestrates lipogenic and glycolytic programs, sustains lysosomal biogenesis and autophagic flux, and governs cell-fate decisions by restraining apoptosis and ferroptosis through iron and redox control. Beyond tumor-intrinsic roles, NUPR1 remodels the tumor microenvironment by driving immunosuppressive macrophage polarization and amplifying inflammatory signaling, collectively sustaining a pro-survival niche. These circuits underpin broad therapeutic resistance across modalities, spanning chemotherapy, targeted agents, endocrine therapy, and immune checkpoint blockade. We further discuss the development of small-molecule NUPR1 antagonists-including ZZW-115 and emerging chemotypes-that disrupt nuclear trafficking and stress tolerance, alongside formulation strategies to optimize pharmacodynamic potency and safety. Together, these insights establish NUPR1 as a druggable stress-response node and provide a mechanistic framework to overcome resistance and refine adaptive cancer therapy paradigms.

Address: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, China.; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, China.; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, China.; Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, 310018, China.; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Translational Research and Therapeutic Targets in Pancreatic Cancer, Marseille, France. [email protected].; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, China. [email protected].

DOI: 10.1186/s12929-026-01254-x

MeSH Terms: Humans, Neoplasms, Drug Resistance, Neoplasm, Basic Helix-Loop-Helix Proteins, Neoplasm Proteins, Cell Death, Tumor Microenvironment, Stress, Physiological