2. Academic Validation
  3. Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer

Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer

  • Cell Death Discov. 2026 Jan 19;12(1):86. doi: 10.1038/s41420-026-02940-3.
Silvia Sabbioni # 1 2,  Paola Guerriero # 3,  Ram C Shankaraiah # 3 4,  Laura Masatti 3 5,  Angelo Michilli 3,  Cristian Bassi 6 3,  Lucilla D'Abundo 3,  Farzaneh Moshiri 3,  Bruno De Siena 7,  Edi Simoni 3 8,  Laura Astolfi 8,  Laura Gramantieri 9,  Roberta Roncarati 3 10,  Bahaeldin K Elamin 11 12,  Massimo Bonora 13,  Paolo Pinton 13,  Carlo M Croce 14,  Massimo Negrini 15 16,  Elisa Callegari 17
Affiliations

Affiliations

  • 1 Department of Life Sciences and Biotechnology, University of Ferrara, 44121, Ferrara, Italy. [email protected].
  • 2 Laboratorio Per Le Tecnologie Delle Terapie Avanzate (LTTA), University of Ferrara, 44121, Ferrara, Italy. [email protected].
  • 3 Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy.
  • 4 Glaxo Smith Kline - Wavre Belgium Av. Fleming 20, 1300, Wavre, Belgium.
  • 5 Department of Biology, University of Padova, 35100, Padova, Italy.
  • 6 Laboratorio Per Le Tecnologie Delle Terapie Avanzate (LTTA), University of Ferrara, 44121, Ferrara, Italy.
  • 7 Department of Life Sciences and Biotechnology, University of Ferrara, 44121, Ferrara, Italy.
  • 8 Bioacoustics Research Laboratory, Department of Neurosciences, University of Padova, 35129, Padova, Italy.
  • 9 Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy.
  • 10 CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Bologna, Italy.
  • 11 Department of Microbiology and Clinical Parasitology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia.
  • 12 Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan.
  • 13 Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.
  • 14 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • 15 Laboratorio Per Le Tecnologie Delle Terapie Avanzate (LTTA), University of Ferrara, 44121, Ferrara, Italy. [email protected].
  • 16 Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy. [email protected].
  • 17 Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy. [email protected].
  • # Contributed equally.
PMID: 41554703 DOI: 10.1038/s41420-026-02940-3
Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related death worldwide. The prognosis is poor, with a median survival of 12-15 months in patients with advanced-stage disease. Early diagnosis and the development of new, more effective therapeutic strategies are needed to address the challenges posed by this malignancy. Although immune checkpoint inhibitors have replaced multikinase inhibitors as first-line therapy, sorafenib continues to represent a valuable option for patients with contraindications to newer treatments. Based on genome-wide RNA-seq analysis, which identified mitochondrial Oxidative Phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver Cancer models. Co-treatment with SR9009 and sorafenib significantly enhanced cytotoxic effects in both mouse and human liver Cancer cells. This synergistic activity was associated with increased levels of free heme and a complete inhibition of mitochondrial OxPhos. In vivo xenograft studies confirmed that the combination was effective even in sorafenib-resistant tumors. Furthermore, in a N-Nitrosodiethylamine (DEN)-induced HCC model, the combination therapy led to a reduction in size in over 90% of tumor nodules, representing a significant improvement over sorafenib alone. The combination was well tolerated, with no evident signs of acute toxicity. These findings support the concept that the efficacy of Anticancer therapies can be enhanced by targeting the metabolic adaptations that tumor cells rely on for survival. Combining sorafenib with agents like SR9009, that disrupt metabolic homeostasis, may offer a promising strategy for treating advanced HCC.

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