Targeting the Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma

Authors

Baharan Fekry
Savera Aggarwal
Rachel Van Drunen
Rafael Bravo
Andy Escalante
Constance Atkins
Sheng Pan
Zheng Chen
Kai Sun
David R Hall
Mamoun Younes
Kristin Eckel-Mahan

Language

English

Publication Date

11-25-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.116313

PMID

41124076

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.

Keywords

Carcinoma, Hepatocellular, Liver Neoplasms, Humans, Circadian Clocks, Animals, ARNTL Transcription Factors, Protein Kinase Inhibitors, Mice, Carnitine O-Palmitoyltransferase, Flavones, Cell Line, Tumor, Liver, Male, BMAL1, CP: Cancer, CP: Metabolism, CPT1A, HNF4α, acylcarnitine, chronotherapy, circadian, hepatocellular carcinoma, metabolism, nobiletin, tyrosine kinase inhibitors

Published Open-Access

yes

Recommended Citation

Fekry, Baharan; Aggarwal, Savera; Van Drunen, Rachel; et al., "Targeting the Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma" (2025). Faculty, Staff and Student Publications. 5607.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5607