Targeting the hepatic circadian clock concomitant with tyrosine kinase inhibition reverses late-stage hepatocellular carcinoma

Authors

• Baharan Fekry, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: baharan.fekry@uth.tmc.edu.
• Savera Aggarwal, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Rachel Van Drunen, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Rafael Bravo, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Andy Escalante, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Constance Atkins, Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
• Sheng Pan, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Zheng Chen, Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• Kai Sun, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
• David R. Hall, Department of Surgery, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, USA.
• Mamoun Younes, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
• Kristin Eckel-Mahan, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: kristin.l.mahan@uth.tmc.edu.

Document Type

Journal Article

Publication Date

10-20-2025

Journal

Cell reports

Volume

44

Issue

11

DOI

10.1016/j.celrep.2025.116313

Keywords

BMAL1; CP: Cancer; CP: Metabolism; CPT1A; HNF4α; acylcarnitine; chronotherapy; circadian; hepatocellular carcinoma; metabolism; nobiletin; tyrosine kinase inhibitors

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase expression and related metabolite abundance and that P2-HNF4α regulates the carnitine palmitoyl transferase I gene. Finally, using different preclinical models, we show that the anti-tumor activity of TKIs, when they are co-administered with NOB, is maximal. Our results suggest that chronotherapy and combination therapy might provide improved clinical outcomes for individuals with BMAL1-deficient HCC.

APA Citation

Fekry, Baharan; Aggarwal, Savera; Van Drunen, Rachel; Bravo, Rafael; Escalante, Andy; Atkins, Constance; Pan, Sheng; Chen, Zheng; Sun, Kai; Hall, David R.; Younes, Mamoun; and Eckel-Mahan, Kristin, "Targeting the hepatic circadian clock concomitant with tyrosine kinase inhibition reverses late-stage hepatocellular carcinoma" (2025). GW Authored Works. Paper 8256.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8256

Department

Pathology