Circadian clock protein promotes inflammation — Nuclear transport of MFP2 enzyme advances cancer progression

Although it was known that the circadian clock regulates immune cells, the detailed mechanism remained unknown. A research group including Lecturer Akito Tsuruta, Professor Naoya Matsunaga, Professor Satoru Koyanagi, and Special Appointed Professor Shigehiro Ohdo of the Graduate School of Pharmaceutical Sciences at Kyushu University has clarified that BMAL1, which is a protein playing a central role in the circadian clock, binds to MFP2, a fatty acid-decomposing enzyme present in peroxisomes, and transports it into the cell nucleus. This process produces acetyl-CoA and activates the transcription factor NF-κB, thereby inducing macrophages to shift toward a pro-inflammatory phenotype (M1 type). The findings were published in Cell Reports.

The impact of clock genes on inflammation has been known for a long time. For example, rheumatism causes stiffness symptoms in the morning. While anti-inflammatory drugs, such as steroids and non-steroidal anti-inflammatory drugs (NSAIDs), have been developed to address this, many diseases still cannot be suppressed by these treatments, necessitating the development of anti-inflammatory drugs based on a new mechanism of action.

To analyze the relationship between inflammatory responses and the circadian clock mechanism, and to clarify a new inflammation control mechanism, the research group has been working on this research for about 10 years, focusing particularly on macrophages.

First, water containing diethylnitrosamine (DEN) was administered for 13 weeks to normal mice and to macrophage-selective BMAL1 knockout mice. As a result, both inflammatory markers and liver cancer markers were suppressed, and tumor growth was inhibited in the knockout mice. In other words, they found that BMAL1 in macrophages promotes inflammation and fuels the development of liver cancer.

To elucidate this mechanism, the group used mass spectrometry to analyze nuclear proteins that bind to BMAL1, discovering that the peroxisomal (a type of organelle) β-oxidation enzyme MFP2 binds to BMAL1 and is transported into the nucleus. MFP2 is an enzyme that decomposes very-long-chain fatty acids in peroxisomes to produce acetyl-CoA, which is involved in protein function regulation and energy production.

When the amount of nuclear acetyl-CoA in MFP2-deficient macrophages was measured, it was significantly decreased compared to normal cells. It is known that the activity of p65, a constituent protein of the inflammatory transcription factor NF-κB, is enhanced by acetylation modification using acetyl-CoA as a substrate. In fact, it was confirmed that NF-κB function decreased in MFP2-deficient macrophages.

Through this, they clarified a new mechanism where MFP2, which was previously thought to function only in peroxisomes, is transported into the nucleus by BMAL1, promoting inflammatory responses in macrophages and advancing the progression from chronic hepatitis to liver cancer. Furthermore, it was found that the amount of nuclear MFP2 exhibits a BMAL1-dependent circadian rhythm, with nuclear MFP2 increasing during time zones when nuclear BMAL1 is abundant in the mouse liver.

Tsuruta stated: "By utilizing the time-dependent nature of this mechanism and combining it with chronotherapy, which considers the optimal timing of drug administration, we hope to lead the way toward developing new therapeutic strategies against inflammatory diseases and cancer. Additionally, we have identified a substance that can inhibit the function of nuclear MFP2. We will proceed with validations in human macrophages and patient tissues to connect this to therapeutic drug development."

Journal Information
Publication: Cell Reports
Title: The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2
DOI: 10.1016/j.celrep.2026.117480