<p>Ferroptosis is reported to be closely involved in acetaminophen (APAP) overdose induced liver injury. The development of hepatoprotective drugs that target ferroptosis inhibition is highly valuable. In our previous work, we have confirmed the antioxidant properties of syringaresinol (SYR), but its effects on ferroptosis and the potential molecular mechanisms are unclear. This study aimed to investigate the impact of SYR on APAP-induced hepatocyte ferroptosis and elucidate the role of Caveolin-1 (CAV-1) in the protective function of SYR, focusing on its regulation of the Nrf2/HO-1 signaling pathway. In vitro validation was performed in APAP-treated AML12 and HL7702 cells. A mouse model of acute liver injury was established using intraperitoneal APAP injection. SYR was administered at low and high doses. We found that SYR significantly reduced ROS accumulation and Fe²⁺ overload, thereby alleviating APAP-induced cell death in vitro. Similarly, SYR alleviated APAP-induced liver injury by decreasing the level of Fe²⁺ and lipid peroxidation in mice. Western blot analysis also demonstrated SYR’s suppression of APAP-induced ferroptosis. Furthermore, SYR treatment dramatically elevated the protein expression of CAV-1 and activated the Nrf2/HO-1 pathway. Most importantly, knockdown of CAV-1 markedly abolished the protective effects of SYR against APAP-induced hepatocyte ferroptosis, as well as its activation effect on Nrf2/HO-1 pathway, indicating its critical role in SYR’s function on ferroptosis. Collectively, our results indicate that SYR protects against APAP-induced hepatocyte ferroptosis through the CAV-1/Nrf2/HO-1 signaling pathway.</p> Graphical abstract <p></p>