The Circadian Clock controls Hepatic Inflammation in MASLD.

BACKGROUND & AIMS: The circadian clock dictates time-of-day dependent gene, protein expression, and metabolite levels to ensure liver homeostasis. Circadian misalignment is implicated in the development of various metabolic disorders, but its contribution to the progression of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) toward Metabolic dysfunction-Associated Steatohepatitis (MASH) remains poorly understood. Here, we aimed to dissect the role of the circadian clock in MASH development. METHODS: Using an environmental model of chronic circadian misalignment (n=6-12/group), combined with metabolic and immune phenotyping, single nuclei transcriptomics and lipidomic profiling, we investigated the role of the clock in MASLD development and hepatic inflammation. To dissect the specific contribution of the immune clock, we used a genetic model overexpressing the clock component Rev-erbα in myeloid cells (n=3-5/group). RESULTS: Chronic circadian misalignment combined with a high-fat, high-sucrose, cholesterol-enriched (HFHSC) diet markedly amplified hepatic inflammation, characterized by the upregulation of pro-inflammatory genes (p<0.01) and increased immune cell infiltration, including the expansion of hepatic lipid-associated macrophages (hLAMs) (p<0.0001). This heightened inflammatory response promoted fibrotic deposition (p<0.0001). Although circadian misalignment did not worsen glucose intolerance or hepatic steatosis, it altered hepatic metabolic gene expression profile, indicating a broad reprogramming of immune and metabolic pathways. Conversely, myeloid-specific Rev-erbα overexpression attenuated hepatic inflammation in HFHSC-fed mice (p<0.05). CONCLUSIONS: The circadian clock controls both hepatic fatty acid profile and inflammatory process, and its misalignment aggravates MASLD by increasing liver inflammation and fibrosis. Targeting circadian regulators such as Rev-erbα in myeloid cells may offer a promising therapeutic avenue for controlling liver inflammation in MASLD. IMPACT AND IMPLICATIONS: By combining environmental and genetic approaches, this study highlights the central role of the circadian clock in regulating hepatic inflammation during MASLD progression. These findings underscore the importance of considering biological rhythms in the prevention of chronic metabolic diseases and support the potential of circadian clock-targeted strategies as a novel therapeutic avenue.