Obesity is an independent risk factor for acute respiratory distress syndrome (ARDS). However, the precise pathway through which obesity amplifies the severity of ARDS remains elusive. Our study embarked on a comprehensive analysis focusing on alterations in the proteomic landscapes of lung tissue extracted from high-fat diet (HFD) mice afflicted with lipopolysaccharide-induced lung injury. This approach was designed to shed light on the molecular mechanisms underlying the exacerbated pulmonary response in obesity-related ARDS.