Background: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) form a “bidirectional vicious cycle” through the gut–brain axis: psychological and emotional abnormalities can induce intestinal inflammation, while intestinal inflammation can in turn exacerbate mental health disorders. Ferroptosis is an iron-dependent form of regulated cell death that is driven by lipid peroxidation. Although this process has been molecularly defined in recent years, its role in the context of IBD and MDD remains insufficiently investigated. This study investigates the molecular roles of ferroptosis-related genes (FRGs) in both conditions and explores potential therapeutic strategies targeting these genes. Methods: We first identified differentially expressed FRGs (DE-FRGs) by comparing normal and disease samples. Subsequently, we screened for DE-FRGs in both IBD and MDD and named them Co-DEGs. Correlation analyses of these co-FRGs were performed, including comparisons between disease and control groups, as well as associations between Co-DEGs and immune cell infiltrations. Four distinct machine learning algorithms were employed to identify the core Co-DEGs associated with both IBD and MDD. Moreover, analyses of drug sensitivity, molecular docking, and molecular dynamics simulations were carried out to predict potential therapeutic agents for both conditions. Finally, single-cell sequencing analysis was also performed. Results: We identified 29 Co-DEGs in both IBD and MDD. Machine learning analysis identified RPL8 as a key common biomarker exhibiting a consistent expression trend in both diseases. A predictive approach integrating molecular docking and molecular dynamics simulations indicated that LE135, a compound targeting RPL8, is the most promising therapeutic candidate. Conclusions: These discoveries enhance the understanding of the shared and distinct regulatory mechanisms of FRGs in gut–brain axis disorders. We have pinpointed key biomarkers and predicted potential therapeutic agents that may offer dual-targeting strategies for both 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.