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

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

11-25-2025

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.

Department

Pathology

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