Necroptosis is closely associated with the development of inflammatory diseases, including acute liver injury. However, the precise role of necroptosis-related signature proteins in acute liver injury remains incompletely understood. Previously, our group investigated Compound o1, a RIP1 inhibitor, but its antinecroptosis activity and RIP1 binding affinity were suboptimal. In this study, we sought to address these two critical scientific challenges. Through a scaffold-hopping strategy, we identified a series of novel quinoline-like RIP1 inhibitors, among which N-1 exhibited the most potent antinecroptosis activity and the strongest RIP1 binding affinity. N-1 effectively inhibited necrosome formation by blocking phosphorylation in the RIP1/RIP3/MLKL signaling pathway. In a TNF-induced hypothermia mouse model of systemic inflammatory response syndrome (SIRS), N-1 significantly improved the survival rate of mice in a dose-dependent manner. Our study further revealed that RIP1, RIP3, and MLKL are expressed in normal liver tissues, whereas their phosphorylated forms (pRIP1, pRIP3, and pMLKL) are absent. In contrast, liver tissues from mice with CCl