Daily life is shaped by the solar day, which affects when you wake up, eat, work, and sleep. Inside the body, a similar internal timing system known as the circadian clock, present in nearly every cell, synchronizes many biological functions, including sleep, metabolism, hormone release, and even immune system activity. Now, researchers at Kyushu University have elucidated a previously unknown mechanism by which a circadian clock protein called brain-muscle ARNT-like 1 (BMAL1) enhances the inflammatory response of immune cells. The findings provide new insights into how the body clock influences immune responses and could pave the way for new approaches to treating inflammatory diseases and cancer.
When our bodies encounter injury or infection, the immune system dispatches cells known as macrophages to initiate an inflammatory response that begins the healing process. These macrophages can exist in two different states: a pro-inflammatory (M1) state, which promotes inflammation, and an anti-inflammatory (M2) state, which helps resolve inflammation and repair tissue. The balance between these two conditions is important. When this breaks down, inflammation can get out of control, leading to chronic inflammation-related diseases such as cancer, liver disease, diabetes, and autoimmune diseases.
Previous studies have shown that macrophage activity is closely linked to the circadian clock and that BMAL1 plays a central role in regulating this process. In a study published in a journal cell report On June 9, 2026, a research team consisting of Lecturer Akito Tsuruta, Professor Naoya Matsunaga, Professor Satoru Koyanagi, and Specially Appointed Professor Shigehiro Daido from the Kyushu University Faculty of Pharmaceutical Sciences discovered that BMAL1 induces macrophages into the pro-inflammatory M1 state by activating the inflammatory signaling pathway in the cell nucleus.
We discovered a fundamentally new concept in which the circadian clock controls inflammation not only through direct transcriptional regulation but also through nuclear lipid metabolism. This concept links the circadian clock to intracellular metabolism and immune function. ”
Lecturer Akito Tsuruta, Kyushu University
To investigate the role of BMAL1 in macrophage inflammation, researchers generated macrophage-specific BMAL1-deficient mice and exposed them to the chemical carcinogen diethylnitrosamine, which induces liver inflammation and tumor formation.
The research team observed that normal mice showed a marked increase in pro-inflammatory M1 macrophages along with elevated inflammatory signals after exposure. In contrast, mice lacking BMAL1 in macrophages had significantly reduced inflammation and suppressed liver tumor development.
To understand the molecular basis of these effects, the research team used mass spectrometry to analyze proteins that interact with BMAL1 in the nucleus. Their experiments revealed that BMAL1 binds multifunctional protein 2 (MFP2), a fatty acid oxidase normally found in cellular compartments called peroxisomes, and transports it to the cell nucleus. Once in the nucleus, MFP2 increases acetyl-CoA levels and promotes the acetylation of key proteins, including p65, a component of the transcription factor NF-κB, a key regulator of inflammatory genes. This activates NF-κB, which acts as a switch for inflammatory genes, thereby shifting macrophages into a pro-inflammatory M1 state.
Remarkably, nuclear MFP2 levels vary with time of day in a BMAL1-dependent manner. In the livers of control mice, nuclear MFP2 increased during the period when BMAL1 levels were highest, but this rhythmicity was abolished in BMAL1-deficient mice.
These findings suggest that targeting or blocking nuclear MFP2 and administering drugs at optimal times of the day may represent a new therapeutic strategy for chronic inflammatory diseases, increasing therapeutic efficacy while minimizing side effects.
“In the future, we aim to test this mechanism in human cell and tissue samples. We also aim to investigate whether timing the drug with peak nuclear MFP2 levels can help improve outcomes in models of inflammatory diseases and cancer.” conclusion Tsuruta.
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Reference magazines:
Tsuruta, A., others. (2026). BMAL1, a component of the circadian clock, enhances macrophage inflammation through nuclear translocation of the peroxisomal β-oxidase MFP2. cell report. DOI: 10.1016/j.celrep.2026.117480. https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00558-9
