<p>Sepsis-induced acute lung injury is a significant clinical challenge with high morbidity and mortality rates. Currently, no effective therapeutic interventions are available. The aim of this study was to elucidate the role and underlying mechanisms of Caveolin-2 in sepsis-induced acute lung injury. To this end, a Caveolin-2 knockdown model was utilized both in vivo and in vitro, facilitating a comprehensive evaluation of several parameters, including lung tissue injury, inflammatory responses, oxidative stress markers, changes in apoptotic protein expression, and indicators of macrophage polarization. Additionally, the study investigated alterations in proteins associated with the Hippo signaling pathway and assessed the effects of Hippo pathway inhibitors on apoptosis and polarization. Our results indicate that the knockdown of Caveolin-2 facilitates the polarization of macrophages towards the protective M2 macrophage polarization and mitigates macrophage apoptosis. This process is associated with a reduction in oxidative stress and inflammatory responses, culminating in the activation of the Hippo signaling pathway. Conversely, the overexpression of Caveolin-2 intensifies inflammation and oxidative damage, while promoting apoptosis and M1 macrophage polarization. Our findings provide novel insights into the role of Caveolin-2 and Hippo signal pathway in sepsis-induced acute lung injury and establish a foundation for future research and the development of potential therapeutic strategies.</p>