ObjectiveTo explore the causal relationship between immune cells and heart failure (HF), and the mediating role of serum metabolites, in order to identify potential biomarkers and therapeutic targets. MethodsWe employed a two-sample Mendelian randomization (MR) analysis method based on genome-wide association study (GWAS) data, analyzing the direct and indirect effects of 731 types of immune cells and 1 400 metabolites on HF. We selected valid instrumental variables and conducted statistical analyses using R software. The primary analysis was performed using the inverse variance weighted method, supplemented by MR-Egger analysis and weighted median method. The stability of the results was assessed through tests such as Cochran’s Q test. ResultsOur research found a negative causal relationship between PD-L1 on CD14−CD16+ and HF. Sensitivity analysis supported this result. The reverse MR analysis did not find an effect of HF on PD-L1 on CD14−CD16+, indicating that PD-L1 on CD14−CD16+ may play a unidirectional role in reducing the risk of HF. Further mediation MR analysis showed that PD-L1 on CD14−CD16+ might influence the risk of HF onset by regulating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), with a mediation effect ratio of 6.7%. ConclusionPD-L1 on CD14−CD16+ may reduce the risk of HF by elevating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), which provides a new perspective for understanding the pathogenesis of HF.
Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes and a leading cause of vision loss. Recent studies have shown that inflammation and oxidative stress play central roles in its development and progression. Hyperglycemia activates systemic immune cells and retinal resident cells, inducing the release of various inflammatory mediators and chemokines, which disrupt the blood-retinal barrier, leading to capillary leakage and neurodegenerative changes. Meanwhile, the positive feedback loop between inflammation and reactive oxygen species/nitric oxide further amplifies pathological damage, explaining the limited efficacy of anti-vascular endothelial growth factor monotherapy. Oxidative stress manifests as the excessive generation of free radicals such as reactive oxygen species due to hyperglycemia, directly damaging retinal cells and activating inflammatory signaling pathways, thereby exacerbating vascular damage and neurodegeneration. Future therapeutic strategies should adopt multi-target and multi-link interventions, with particular emphasis on the combined application of anti-inflammatory and antioxidant treatments, such as immunomodulation, macrophage phenotype regulation, intervention in the neutrophil extracellular trap axis, and combination therapy using anti-vascular endothelial growth factor drugs and antioxidants, to more effectively intervene in the pathological progression of DR.