Evidence map›Paper›PMID 41124076›Full record

ArticleCell reports2025

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

Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Hepatocellular Carcinoma Around the Clock.Current oncology (Toronto, Ont.) · 2026
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Baharan FekryInstitute 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 AggarwalInstitute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
Rachel Van DrunenInstitute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
Rafael BravoInstitute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
Andy EscalanteInstitute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
Constance AtkinsDepartment of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Sheng PanInstitute 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 ChenDepartment of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA.
Kai SunInstitute 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 HallDepartment of Surgery, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, USA.
Mamoun YounesDepartment of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Kristin Eckel-MahanInstitute 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.

Funding

Complement and Circadian Interactions in Inflammation and ImmunityR01AI158694 · NIAID · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MAHAN, KRISTIN ECKEL, SHIVSHANKAR, POOJA · 2021 to 2025
$1.9M
Origins of Diet-Induced Circadian Reprogramming and PlasticityR01DK114037 · NIDDK · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MAHAN, KRISTIN ECKEL · 2018 to 2022
$1.9M
NIAID NIH HHS R01 AI158694NIDDK NIH HHS R01 DK114037
6 · The paper itself

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.

Indexed as

Carcinoma, HepatocellularCircadian ClocksLiverLiver NeoplasmsProtein Kinase InhibitorsAnimalsARNTL Transcription FactorsCarnitine O-PalmitoyltransferaseCell Line, TumorFlavonesHumansMaleMiceARNTL Transcription FactorsBMAL1 protein, humanCarnitine O-PalmitoyltransferaseFlavonesnobiletinProtein Kinase InhibitorsacylcarnitineBMAL1chronotherapycircadianCP: CancerCP: MetabolismCPT1Ahepatocellular carcinomaHNF4αmetabolismnobiletintyrosine kinase inhibitors

Identifiers

PMID41124076
PMCPMC13660736

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.