Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca 2+ ‐CaMKK2‐AMPK Signaling to Counter MASLD

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects approximately one‐third of adults and lacks effective pharmacological therapies. Here, we identify Chromobox 2 (CBX2), a Polycomb‐associated chromatin regulator, as a previously unrecognized regulator of hepatic lipid homeostasis. CBX2 expression is markedly reduced in hepatocytes from patients with MASLD, multiple mouse models ( db/db , ob/ob , HFD, and HFHC), and steatotic hepatocytes in vitro . Hepatocyte‐specific CBX2 overexpression ameliorates hepatic steatosis, improves glucose metabolism, and suppresses inflammation, whereas CBX2 deficiency exacerbates these metabolic disturbances. Mechanistically, CBX2 enhances H3K4me3 enrichment at the Orai1 promoter, promoting Orai1 transcription and increasing intracellular Ca 2+ levels. Elevated Ca 2+ activates the CaMKK2‐AMPK signaling pathway, leading to ACC phosphorylation, inhibition of de novo lipogenesis (FAS, ACC, and SCD‐1), enhancement of fatty acid oxidation (PPARα and CPT‐1a), and suppression of NF‐κB/JNK‐mediated inflammation. Genetic and pharmacological interventions further establish the necessity of this Ca 2+ ‐CaMKK2‐AMPK axis for CBX2‐mediated metabolic protection. Collectively, our findings reveal a CBX2‐driven metabolic regulatory circuit and highlight CBX2 and its downstream signaling pathway as potential therapeutic targets for MASLD.