Amelioration of acute liver failure by a cinnamic acid derivative through inhibition of the ROS-NETosis axis.

Acute liver failure (ALF) represents a critical clinical challenge with limited therapeutic options beyond liver transplantation, urgently requires novel therapeutic strategies. Here, we show that a cinnamic acid derivative, CA7, confers significant protection in mouse models of ALF. The therapeutic benefits of CA7 were evidenced by the preservation of hepatic architecture, reduction of mitochondrial damage and apoptosis, and enhanced survival rates. Using an integrated approach combining single-cell RNA sequencing and functional validation, we found that neutrophils are prominently involved in the hepatic response to CA7 treatment and represent a major cellular population through which CA7 exerts its protective effects. Mechanistically, CA7 exerts its potent hepatoprotective effects by selectively suppressing reactive oxygen species production, thereby inhibiting neutrophil extracellular trap formation, a pivotal trigger of hepatic oxidative injury. This intervention attenuated neutrophil recruitment and activation, restored redox homeostasis, and suppressed activation of the NF-κB-NLRP3-IL-1β inflammatory signaling cascade. As a consequence, CA7 effectively alleviated cytokine storm-associated inflammatory responses, prevented mitochondrial dysfunction and protected hepatocyte from apoptosis. Together, these coordinated actions underlie the robust protective effects of CA7 in ALF. Our findings suggest that CA7 acts as a promising therapeutic candidate for ALF and highlight reactive oxygen species (ROS)-dependent NETosis as an important pathogenic process in life-threatening ALF.