2. Academic Validation
  3. The Novel HSF1 Inhibitor NXP800 Exhibits Robust Antitumor Activity in Hepatocellular Carcinoma

The Novel HSF1 Inhibitor NXP800 Exhibits Robust Antitumor Activity in Hepatocellular Carcinoma

  • Int J Mol Sci. 2026 Mar 19;27(6):2781. doi: 10.3390/ijms27062781.
Sara M Steinmann 1 2,  Melania Lazzari 3 4 5,  Augustinus Kleinle 1,  Dora Pischedda 6,  Antonio Cigliano 6 7,  Grazia Galleri 8,  Heiko Siegmund 1,  Claudia Fischer 1,  Salvatore Piscuoglio 3 4,  Matthias Evert 1,  Diego F Calvisi 1
Affiliations

Affiliations

  • 1 Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
  • 2 Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
  • 3 Department of Biomedical Science, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy.
  • 4 IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy.
  • 5 Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, 4001 Basel, Switzerland.
  • 6 Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy.
  • 7 Faculty of Medicine, Saint Camillus International University of Health Sciences, 00131 Rome, Italy.
  • 8 Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
PMID: 41898642 DOI: 10.3390/ijms27062781
Abstract

Heat-shock factor 1 (HSF1) is a multifunctional transcription factor whose overexpression is associated with the development, progression, and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). In the present study, we thoroughly investigated the antitumor activity of NXP800, a recently developed HSF1 Inhibitor that is currently tested in clinical trials, on HCC growth. We discovered that NXP800 inhibits the cell growth of human HCC cell lines by reducing proliferation, inducing Apoptosis, and causing DNA damage. At the metabolic level, NXP800 significantly decreased mitochondrial respiration, which was associated with extensive structural alterations in the mitochondria, and reduced glycolysis of HCC cells. At the molecular level, NXP800 administration led to the upregulation of the integrated stress response and downregulation of the E2F1 signaling cascade. In addition, NXP800 profoundly constrained the growth of HCC patient-derived organoids. Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP Inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC.

Keywords

CCT361814; HCC; HSF1; HSF1 pathway inhibitor; NXP800; heat shock response; hepatocellular carcinoma.

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