BMAL1 Transports MFP2 to Nucleus to Drive Macrophage M1 Polarization and Liver Tumorigenesis in Mice
Mouse genetic and proteomic experiments establish BMAL1-MFP2 nuclear shuttling as a driver of pro-inflammatory macrophage state and chemically induced liver cancer. The work connects circadian timing to intracellular metabolism and NF-κB signaling. Evidence remains limited to rodent models; human relevance and therapeutic timing windows require direct testing.
Kyushu researchers generated conditional knockouts and exposed mice to the carcinogen diethylnitrosamine. Controls developed robust M1 macrophage influx and tumors while BMAL1-deficient animals showed reduced inflammation and fewer tumors. Mass spectrometry identified the peroxisomal enzyme MFP2 as a BMAL1 interactor that is shuttled into the nucleus in a time-of-day-dependent manner, elevating acetyl-CoA and acetylating p65 to amplify inflammatory transcription.
This mechanism integrates circadian transcriptional control with nuclear lipid metabolism, a link not captured by earlier macrophage clock studies focused solely on direct gene regulation. The finding aligns with observational data linking shift work to elevated cancer incidence and with smaller human chronotherapy trials showing time-of-day effects on cytokine responses during checkpoint blockade.
Next steps require human macrophage and organoid validation plus testing whether pharmacological or light-based resetting of BMAL1 rhythms alters tumor incidence in at-risk populations. Without these data, translation to timed interventions remains speculative.
Kyushu group: First-in-human BMAL1 rhythm modulation trial in chronic hepatitis reports ≥20 % drop in serum IL-6 at 6 months.
Sources (2)
- [1]Primary Source(https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00345-6)
- [2]Supporting Source(https://www.nature.com/articles/s41577-023-00892-4)