Caveolin-1 ameliorates hepatic injury in non-alcoholic fatty liver disease by inhibiting ferroptosis via the NOX4/ROS/GPX4 pathway

[Display omitted] Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology.