Emerging evidence links ferroptosis–mitochondrial dysregulation to depression pathogenesis through an oxidative stress–energy deficit–neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal–hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a “ferroptosis–mitochondrial fragmentation–metabolic maladaptation” triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability—a framework with significant implications for developing neuroprotective antidepressants.

Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE^-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).

Background: The diagnosis, treatment, and prevention of atherosclerosis co-depression are poor, so it is urgent to explore new targets. Based on the “microbiota-gut-brain axis,” this study aimed to investigate the changes of lipid metabolites in the prefrontal cortex and hippocampus regions and the characteristics of the gut microbiota in ApoE^−/− mice with atherosclerosis co-depression.Methods: ApoE^−/− mice (hyperlipid feeding combined with binding, HFB group, n = 14, male) fed a high-fat diet for 16 weeks with binding stimulation were used as an animal model for atherosclerosis co-depression. The depression degree of mice was evaluated by body weight, sucrose preference test, open field test, and tail suspension test. Oil-red O staining, HE staining, and biochemical parameters were used to evaluate the damage degree of atherosclerosis in mice. LC-MS/MS technique for non-targeted lipidomics analysis was used to analyze the differential lipid metabolites in the prefrontal cortex and hippocampus regions of mice. 16S rDNA amplification sequencing was used to screen the differential gut microbial, and association analysis was performed with the differential lipid metabolites.Results: Compared with the normal control group (NC group), the HFB group showed depression-like behaviors and atherosclerosis-related pathological indicators. The differential lipid metabolites in the prefrontal cortex and hippocampus regions were mainly LPC, LPE, LPS, PC, PE, PS, PI, and GD1a, and were mainly enriched in the glycerophospholipid metabolism pathway and the retrograde endocannabinoid signaling pathway. At the same time, there were significant differences in the structure of the gut microbial community between the two groups. The abundance of Deferribacteres and Proteobacteria in the HFB group increased, while the abundance of Verrucomicrobia and Actinobacteria decreased at the phylum level; the abundance of Desulfovibrio, Clostridium_IV, Helicobacter and Pseudoflavonifractor increased, while the abundance of Akkermansia decreased at the genus level.Conclusion: Atherosclerosis co-depression of ApoE^−/− mice of the prefrontal cortex and hippocampus lipid metabolism pathways of disorder and the changes of to the gut microbiota, which leads to abnormal white matter and synaptic dysfunction, increased gut inflammation, and decreased gut permeability, leading to the release of inflammatory cytokines, there is a strong correlation between both, it further confirmed the existence of the “microbiota-gut-brain axis.”

Background: Atherosclerosis (AS) concomitant depression is a serious clinical problem with unclear mechanisms of co-morbidity. Baicalin (BA) can resist atherosclerosis and depression by regulating intestinal flora and host lipid metabolism. Therefore, based on intestinal microorganisms and lipid metabolism, this study explored the mechanism of baicalin against AS concomitant depression.Methods: 16 C57BL/6 mice were fed with normal diet as blank control group. 48 ApoE^-/-mice were randomly divided into 3 groups (model group and BAL, BAH two treatment groups). The mouse model of atherosclerosis concomitant depression was established by high-fat feeding combined with restraint stimulation for 16 weeks. Behavioural experiments and biochemical indexes were used to detect the antidepressant effect and anti-atherosclerosis effect of baicalin. Metagenomic sequencing technology combined with metabolomics analysis was used to detect the effects of BA on intestinal microflora structure and brain lipids in AS co-depressed mice. Erastin was used to induce HT-22 hippocampal neurons to construct a model of ferroptosis. The inhibition of baicalin on ferrotosis was verified by detecting the cell viability, ROS production, and expression levels of glutathione, SLC7A11, GPX4 and ACSL4 in each group.Results: Baicalin could effectively improve the indexes of AS co-depressed mice, and the results of metagenomics and lipidomics showed that there were disorders of intestinal flora represented by Helicobacter_typhlonius and Escherichia_coli and disorders of lipid metabolism represented by PE in the AS co-depressed model mice. The correlation analysis showed that the lipid metabolism disorders in the model mice were closely related to the intestinal flora disorders, and baicalin intervention could effectively improve the intestinal flora and lipid metabolism disorders in the AS co-depressed mice. Metabolic pathway enrichment analysis showed that differential lipid PEs were significantly enriched in the iron death pathway, and our further in vitro cellular experiments showed that baicalin could inhibit Erastin-induced Ferroptosis in the hippocampal neuronal cell line HT-22 by promoting the expression of SLC7A11, GSH, and GPX4, inhibiting the expression of ACSL4, and decreasing the cellular ROS.Conclusion: Baicalin improves intestinal microbiota and brain lipid metabolism and inhibits ferroptosis of nerve cells, which possesses the application value of anti-atherosclerotic concomitant depression.

Atherosclerosis (AS)-related cardiovascular disease and depression are often comorbid, with patients with cardiovascular disease facing an increased risk of depression, which worsens AS. Both diseases are characterized by oxidative stress and lipid metabolism disorders. Ferroptosis, a form of cell death characterized by iron overload and harmful lipid peroxide accumulation, is found in various diseases, including AS and depression. Consistent with the iron deposition and lipid peroxidation (LPO) that characterize the ferroptosis mechanism, disturbances in iron and lipid metabolism are also crucial pathogenic mechanisms in AS and depression. The comorbid mechanisms are complex, posing challenges for clinical treatment. Chinese herbs hold significant potential owing to their multi-target pharmacological effects. Therefore, this review aims to investigate iron overload, LPO, and ferroptosis across various cell types, the shared pathogenesis of AS and depression with ferroptosis, and research on Chinese herbal medicine targeting ferroptosis in the treatment of anti-AS co-depression. This provides a comprehensive understanding of AS co-depression disease from the perspective of ferroptosis.