Defects in Aryl hydrocarbon receptor nuclear translocator-like 1 (ARNTL), a central component of the circadian clock mechanism, may promote or inhibit the induction of inflammation by monocytes/macrophages, with varying effects on different diseases. However, ARNTL’s role in monocytes/macrophages under chronic kidney disease (CKD), which presents with systemic inflammation, is unclear. Here, we report that the expression of Arntl in monocytes promoted CKD-induced cardiac damage. The expression of G-protein-coupled receptor 68 (GPR68), which exacerbates CKD-induced cardiac disease, was regulated by ARNTL. Under CKD conditions, GPR68 expression was elevated via ARNTL, particularly in the presence of PU.1, a transcription factor specific to monocytes and macrophages. In CKD mouse models lacking monocyte-specific ARNTL, GPR68 expression in monocytes was reduced, leading to decreased cardiac damage and fibrosis despite no improvement in renal excretory capacity or renal fibrosis and increased angiotensin II production. The loss of ARNTL did not affect the expression of marker molecules, indicating the origin or differentiation of cardiac macrophages, but affected GPR68 expression only in cardiac macrophages derived from mature monocytes, highlighting the significance of the interplay between GPR68 and ARNTL in monocytes/macrophages and its influence on cardiac pathology. Understanding this complex relationship between circadian clock mechanisms and disease could help uncover novel therapeutic strategies.

5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent for breast cancer. Its efficacy relies on the function of p53, and mutations in p53 contribute to the development of resistance during 5-FU chemotherapy. Here, we report that microcurrent stimulation (MCS) of a p53-mutant breast cancer cell line induces p53-mediated cell death. Although MDA-MB-231 and MDA-MB-468 cells, both human breast cancer cell lines, are less sensitive to 5-FU due to p53 mutations, MCS (300 μA for 30 min) induced apoptosis in these cells and improved the antitumor effect of 5-FU in tumor-bearing mice. MCS-induced apoptosis was mediated by an increase in intracellular Cu²⁺ ions and reactive oxygen species, along with the concurrent transcriptional enhancement of pro-apoptotic genes by p53. Furthermore, MCS induced apoptosis in MDA-MB-231 cells that had developed resistance to 5-FU and inhibited tumor growth in tumor-bearing mice with reduced 5-FU sensitivity. These findings suggest that an approach involving MCS could serve as a foundation for developing breast cancer treatment strategies to overcome p53 mutations.

The present review discusses vitamin A/retinoid metabolism as a cross-organ axis in which hepatic clock-dependent retinoid handling may affect immune clock gene expression through the stimulation of retinoic acid 6–Janus kinase 2–signal transducer and activator of transcription 5 signaling, potentially promoting pro-inflammatory monocyte states. We further highlight mechanosensory signaling as a second convergent layer that integrates hemodynamic forces with tissue microenvironmental cues. Among these pathways, G protein-coupled receptor 68, a proton- and flow-sensitive G protein-coupled receptor, is discussed as a representative druggable node linking mechanical and inflammatory signaling in chronic kidney disease-associated cardiac injury. Finally, we outline potential therapeutic directions, including (i) circadian alignment/chronopharmacology, (ii) modulation of retinoid metabolism and signaling, and (iii) targeted inhibition of primary immune and mechanosensory effectors.