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The functions of the Rspo-LGR system in differentiated cells remain uncharacterized. In this study, the expression profiles of LGRs and Rspos were characterized in mature hepatocytes. A liver-specific knockout of LGR4 in mouse was generated and used to study hepatic ischemia\/reperfusion-induced injury (HIRI) as well as lipopolysaccharide\/ D- galactosamine (LPS\/D-Gal)-induced liver injury. We have demonstrated that, in adult liver, LGR4 is expressed in hepatocytes and responds to Rspo1 with internalization. Rspo1 is responsive to various nutritional states and to mTOR signaling. Activation of LGR4 by Rspo1 significantly reduced tumor necrosis factor-\u03b1 (TNF\u03b1)-induced cell death, and levels of NF-\u03baB-p65 and caspase-3 in cultured hepatocytes. Knockdown of hepatic LGR4 rendered hepatocytes more vulnerable to TNF\u03b1-induced damage in cultured primary cells and in the setting of HIRI and LPS\/D-Gal-induced liver injury. Rspo1 potentiated both basal and Wnt3a-induced stabilization of \u03b2-catenin. Disruption of \u03b2-catenin signaling reversed the protective effects of Rspo1 on TNF\u03b1-induced hepatocyte toxicity. LGR4 knockdown increased nuclear translocation of NF-\u03baB-p65 in response to acute injury. Overexpression of IKK\u03b2 attenuated the protective effects of Rspo1 on TNF\u03b1-induced cell death. In conclusion, the Rspo1-LGR4 system represents a novel pathway for cytoprotection and modulation of stress-induced tissue damage. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY Functional LGR4 is present in mature hepatocytes. R-spodin1 protects hepatocytes from tumor necrosis factor-\u03b1-induced cell death. Liver-specific knockdown of LGR4 renders liver more susceptible to acute injury. 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