Zhongchun Liu

The recently conceptualized Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a pressing global health burden, characterized by a vicious cycle of dysfunction among the cardiac, renal, and metabolic systems. Growing evidence suggests that gut microbiota dysbiosis, specifically, a loss of butyrate-producing bacteria (BPB) and the resulting systemic butyrate deficiency, may be an important but previously overlooked driver of CKM progression. In this review, we synthesize available evidence linking butyrate to the integrated, multi-organ pathophysiology of CKM and propose a conceptual framework we term the gut-butyrate-CKM axis. We discuss the multiple mechanisms by which butyrate and BPB exert protective effects, including targeting key pathophysiological features of CKM, such as insulin resistance (IR), metabolic inflammation, oxidative stress, endothelial dysfunction, renin–angiotensin–aldosterone system (RAAS) overactivation, and gut dysbiosis itself. Through a critical appraisal of human studies, we bring together findings from direct butyrate supplementation, dietary interventions, and microbiota-directed strategies. Based on this, we argue that butyrate serves as a central hub linking gut homeostasis to systemic metabolic and cardiorenal health. By integrating previously fragmented observations into a coherent framework, this review addresses a conceptual gap in our understanding of CKM pathogenesis and points to actionable, microbiota-targeted therapeutic strategies that could help break the disease cycle. Given the current lack of integrated management options for CKM, our work offers insights for future translational research and clinical practice, highlighting butyrate-centered approaches as a potential paradigm shift in CKM care.

Aims: To explore the role and mechanism of X‐linked USP11 in mitochondrial dysfunction associated with depression. Methods: USP11 knockout mice and USP11 overexpression mice in the prefrontal cortex were constructed, and the role of USP11 in mitochondrial dysfunction in depression was evaluated by behavioral tests and quantitative analysis of mitochondrial function changes in the prefrontal cortex. The interaction protein CK2α of USP11 in depression was identified by IP‐MS, and the role of CK2α was confirmed by using the selective inhibitor CX4945. The direct effects of USP11 and CK2α on mitochondrial function were further verified by using primary neurons. Results: USP11 mediates depression‐like behaviors and impairs mitochondrial function in mice. Mechanistically, USP11 binds to and deubiquitinates CK2α, stabilizing its protein level and promoting mitochondrial dysfunction. The selective inhibitor CX4945 reverses the impairment of neuronal mitochondrial function by CK2α. Conclusion: This study demonstrates that USP11 directly binds to and deubiquitinates CK2, affecting mitochondrial function in the mPFC and leading to depressive‐like behaviors in mice.

Background: Vitamin D deficiency is prevalent among individuals with depression; however, clinical findings regarding this association have been inconsistent. Additionally, a significant proportion of depressed patients present with dyslipidemia, yet the interplay between vitamin D status, lipid metabolism, and depression remains poorly understood. We aimed to explore the role of vitamin D in depression and to investigate the potential associations between vitamin D status, lipid metabolism, and depressive symptoms. Methods: We recruited 412 first-episode, drug-naïve patients with depression and 180 age-matched healthy controls. Fasting venous blood samples were collected in the morning to quantify serum vitamin D and lipid profiles. Depressive symptoms were assessed on the day of blood collection using both the Patient Health Questionnaire-9 (PHQ-9) and the 17-item Hamilton Depression Rating Scale (HAMD-17). Spearman's rank correlation was employed to examine associations between serum vitamin D concentrations and depressive symptom severity. Binary logistic regression analysis was subsequently performed to identify potential risk factors for depression. Results: Compared with healthy controls, depressed patients had significantly lower serum vitamin D and high-density lipoprotein cholesterol (HDL-C) levels. This sex-specific pattern showed that male patients had lower vitamin D, while female patients had lower HDL-C. Spearman's correlation analysis revealed significant inverse correlations of vitamin D and triglyceride (TG) with PHQ-9 and HAMD-17 scores among depressed patients. Logistic regression analysis indicated that individuals with higher vitamin D levels had a reduced likelihood of depression compared with those with low vitamin D levels (adjusted odds ratio (OR) = 0.950, 95% confidence interval (CI): 0.920–0.982, p = 0.002). Similarly, subjects with elevated HDL-C levels were associated with a lower likelihood of depression relative to those with diminished HDL-C levels (adjusted OR = 0.317, 95% CI: 0.173–0.583, p < 0.001). Conclusion: Serum vitamin D and HDL-C levels were lower in patients with depression than in healthy individuals. Both vitamin D and HDL-C may be inversely associated with depression.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis involves dynamic changes in glutamatergic signalling. Magnetic resonance spectroscopy can monitor these changes but lacks temporal resolution and cell-type specificity. We investigated whether urinary astrocyte-derived extracellular vesicles (ADEVs) could serve as a non-invasive proxy for brain receptor dynamics. We prospectively collected longitudinal urine and cerebrospinal fluid (CSF) samples from a 30–35-year-old female patient during 34 days of treatment. We isolated ADEVs using a specific protocol and measured GluN1 protein levels. A 30–35-year-old healthy female provided control samples. Wavelet transform analysis of the patient’s GluN1 time series revealed two distinct patterns. First, a low-frequency trend showed declining GluN1 levels over the treatment period, which mirrored the reduction in CSF GluN1 concentrations. Second, a high-frequency oscillation appeared to be coupled with methotrexate infusions, with GluN1 peaks occurring approximately 48 hours after each dose. This secondary increase may reflect drug-induced p53 activation, which promotes the exosomal release of internalised receptors. These findings suggest that urinary ADEVs provide a feasible and informative method to monitor real-time molecular fluxes in the brain.

Many neuropsychiatric disorders are driven by immunity, but the specific underlying mechanisms and how best to exploit them for therapy remain elusive. Here we combine single-cell transcriptomics of dynamic T cell activation states, identification of expression quantitative trait loci, and Mendelian randomization and colocalization analyses to identify causative genes, pathways, and drug targets in Alzheimer's disease (AD) and major depressive disorder (MDD). During CD4⁺ T cell activation, we identify 73 and 156 putative causal genes for AD and MDD, respectively, with over 90% validating in independent datasets. Twenty-nine (13%) identified genes exhibit CD4⁺ T cell specificity and 34 (15%) show temporal causal patterns. Notably, genes with time-specific effects are 7.4- and 6.2-times more likely to exhibit genetic evidence for AD and MDD, respectively. Twenty-one prioritized genes, including RAC1 and PARP1, are targets for potential drug repurposing. This study provides new evidence for the role of immune-mediated mechanisms in neuropsychiatric disorders and prioritizes drug targets.