Background: The prevalence of major depressive disorder (MDD) among patients with inflammatory bowel disease (IBD) is significantly higher compared to the general population, suggesting a potential link between their pathogeneses. Cuproptosis, defined as cell death caused by intracellular copper accumulation, has not been thoroughly investigated in the context of IBD and MDD. This study aims to uncover the molecular mechanisms of cuproptosis-related genes (CRGs) in both conditions and to explore novel therapeutic strategies by the modulation of CRGs. Methods: In this study, we identified differentially expressed CRGs between normal and disease samples. We calculated the correlation among CRGs and between CRGs and immune cell infiltrations across various tissues. Four machine learning algorithms were employed to identify key CRGs associated with IBD and MDD. Additionally, drug sensitivity, molecular docking, and molecular dynamics simulations were conducted to predict therapeutic drugs for IBD and MDD. Results: We identified DLD, DLAT, DLST, PDHB, and DBT as common DE-CRGs, and DLD, LIAS, SLC31A1, SCO2, and CDKN2A as key CRGs associated with both IBD and MDD. Consequently, DLD was recognized as a shared biomarker in both diseases. A total of 37 potential therapeutic drugs were identified for IBD and MDD. Based on the molecular docking and molecular dynamics simulation analyses, barasertib and NTP-TAE684, which target DLAT, were predicted to be the most effective compounds. Conclusions: These findings have substantially enhanced our understanding of the similarities and differences in the regulatory mechanisms of CRGs within brain–gut axis diseases. Key biomarkers have been identified, and potential therapeutic drugs have been predicted to effectively target IBD and MDD.

Acute lung injury (ALI) is a severe pulmonary disorder characterized by the disruption of the alveolar–capillary barrier, leading to impaired oxygenation and pulmonary edema. Current pharmacological interventions primarily involve the use of steroid drugs, oxygen radical scavengers, and bronchodilators. However, the therapeutic efficacy of these interventions remains inconsistent. Canthin-6-ones, a class of tryptophan-derived alkaloids, exhibit anti-inflammatory, antioxidant, and immunomodulatory properties. In this study, we synthesized a novel Canthin-6-one derivative, namely HCX3, and evaluated its potential beneficial effects and underlying mechanisms on ALI. Prior to the experimental study, network pharmacology analysis revealed that HCX3 may exert anti-inflammatory effects in the context of ALI through the regulation of multiple signaling pathways, including the NF-κB pathways. To validate these findings, Lipopolysaccharide (LPS) was employed to stimulate RAW 264.7 macrophages and bone marrow-derived macrophages (BMDMs) to construct cellular models of inflammatory response associated with ALI. Our data demonstrated that exposure to HCX3 significantly inhibited the transcription and the secretion of multiple pro-inflammatory mediators, including IL-1β, IL-6, and TNF-α, in a dose-dependent manner. Additionally, HCX3 reduced LPS-induced phosphorylation levels of p65 and IκB-α in macrophages, indicating an inhibitory effect of the compound on the activation of NF-κB signaling pathway. Collectively, our data suggest that HCX3 exhibits significant anti-inflammatory effects by inhibiting NF-κB-related signaling pathways, providing new insights for ALI treatment.