Cell reportsOct 22, 2025

Resetting the liver’s daily clock along with cancer drug treatment may reverse advanced liver cancer

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 2, 2026

Abstract

Elevated levels of the P2-driven HNF4α isoform in hepatocellular carcinoma (HCC) are linked to enhanced tumor metabolism.

A subset of HCC exhibits increased expression of the P2-driven HNF4α isoform, which represses the BMAL1 transcription factor.
BMAL1-deficient HCC shows heightened expression of carnitine palmitoyl transferase and related metabolites.
P2-HNF4α is involved in regulating the carnitine palmitoyl transferase I gene.
The plant-based flavonoid nobiletin demonstrates robust inhibitory effects on this subtype of HCC.
Combination therapy with nobiletin and tyrosine kinase inhibitors may enhance anti-tumor activity in preclinical models.

Simplified

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.

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Competing interests

Declaration of interests The authors declare no conflicts of interest.

PubMed

Resetting the liver’s daily clock along with cancer drug treatment may reverse advanced liver cancer

Abstract

Full Text

Funding

Competing interests

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