Abstract As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. Receptor interacting protein kinase 1 (RIPK1) plays a key role in regulating cell survival, cell death, and inflammation. Despite extensive research on its involvement in various pathological conditions, the physiological role of RIPK1 remains relatively unexplored. In this study, we identified RIPK1 in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient ( Ripk1 Δhep ) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1 Δhep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1 Δhep mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1 Δhep mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
