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

Oct 22, 2025Cell reports

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

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

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.

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

Abstract

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