Initially identified as an actin-binding protein containing a PSD95-DLG-ZO1 Domain (PZD domain), Synaptopodin 2 (SYNPO2) has long been considered a structural protein ubiquitously expressed in muscular tissues. However, emerging evidence suggests that SYNPO2 performs diverse functions in cancers in addition to its role in microfilament assembly. In most cancers, high SYNPO2 expression is positively correlated with a good prognosis, suggesting its role as a novel tumor suppressor. Abnormal SYNPO2 expression affects autophagy generation, particularly mitophagy induced by low oxidation or viral infection, as well as chaperone-mediated autophagy triggered by microfilament damage. Mechanically, SYNPO2 regulates tumor growth, metastasis, and invasion via activating the PI3K/AKT/mTOR signal and Hippo signaling pathways. Moreover, the subcellular localization, promoter methylation and single nucleotide polymorphism (SNP) of SYNPO2 have been associated with cancer progression and clinical outcomes, highlighting its potential as a prognostic or diagnostic target for this patient population. This review focuses on the role of SYNPO2 in cancer, including its generation, epigenetic modification, subcellular localization, and biological function.

Aims: Heart failure (HF) is a global health issue, with lipid metabolism and inflammation critically implicated in its progression. This study harnesses cutting-edge, expanded genetic information for lipid and inflammatory protein profiles, employing Mendelian randomization (MR) to uncover genetic risk factors for HF. Methods: We assessed genetic susceptibility to HF across 179 lipidomes and 91 inflammatory proteins using instrumental variables (IVs) from recent genome-wide association studies (GWASs) and proteome-wide quantitative trait loci (pQTL) studies. GWASs involving 47 309 HF cases and 930 014 controls were obtained from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium. Data on 179 lipids from 7174 individuals in a Finnish cohort and 91 inflammatory proteins from a European pQTL study involving 14 824 individuals are available in the HGRI-EBI catalogue. A two-sample MR approach evaluated the associations, and a two-step mediation analysis explored the mediation role of inflammatory proteins in the lipid–HF pathway. Sensitivity analyses, including MR-RAPS (robust adjusted profile score) and MR-Egger, ensured result robustness. Results: Genetic IVs for 162 lipids and 74 inflammatory proteins were successfully identified. MR analysis revealed a genetic association between HF and 31 lipids. Among them, 18 lipids, including sterol ester (27:1/18:0), cholesterol, 9 phosphatidylcholines, phosphatidylinositol (16:0_20:4) and 6 triacylglycerols, were identified as HF risk factors [odds ratio (OR) = 1.037–1.368]. Cholesterol exhibited the most significant association with elevated HF risk [OR = 1.368, 95% confidence interval (CI) = 1.044–1.794, P = 0.023]. In the inflammatory proteome, leukaemia inhibitory factor receptor (OR = 0.841, 95% CI = 0.789–0.897, P = 1.08E-07), fibroblast growth factor 19 (OR = 0.905, 95% CI = 0.830–0.988, P = 0.025) and urokinase-type plasminogen activator (OR = 0.938, 95% CI = 0.886–0.994, P = 0.030) were causally negatively correlated with HF, whereas interleukin-20 receptor subunit alpha (OR = 1.333, 95% CI = 1.094–1.625, P = 0.004) was causally positively correlated with HF. Mediation analysis revealed leukaemia inhibitory factor receptor (mediation proportion: 23.5%–25.2%) and urokinase-type plasminogen activator (mediation proportion: 9.5%–10.7%) as intermediaries in the lipid–inflammation–HF pathway. No evidence of directional horizontal pleiotropy was observed (P > 0.05). Conclusions: This study identifies a genetic connection between certain lipids, particularly cholesterol, and HF, highlighting inflammatory proteins that influence HF risk and mediate this relationship, suggesting new therapeutic targets and insights into genetic drivers in HF.

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers. Especially, in clinical samples of glioblastoma, we found that RPN1 was significantly correlated with patient survival. Through mutation landscape analysis, we identified diverse missense mutations in these DRGs, with NCKAP1 exhibiting the highest mutation frequency (5.9% in skin cutaneous melanoma). Additionally, we observed positive correlations between these DRGs and tumor stemness (DNAss DNA stemness score and RNAss RNA stemness score) as well as RNA modifications, particularly m6A modification, in several cancer types. Furthermore, high expression of SLC7A11, RPN1, and NCKAP1 was positively associated with infiltration of T-helper type 2 (Th2) cells in various cancers, while high expression of SLC7A11, SLC3A2, and RPN1 correlated with tumor mutational burden (TMB) in 10, 4, and 8 tumor types, respectively. Utilizing a protein–protein interaction network, we identified the RHO GTPases Activate WASPs and WAVEs pathway as significantly enriched, suggesting the involvement of these DRGs in cancer-related signaling pathways. Collectively, our findings provide novel insights into the molecular mechanisms and clinical implications of DRGs in pan-cancer, highlighting their potential as biomarkers and therapeutic targets for cancer treatment.

The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin‐like modifier], a post‐translational modification of proteins, and its associated ubiquitin‐proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin‐conjugating enzyme E2 (Ubc9), the only SUMO‐E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9‐regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease. image

During the COVID-19 pandemic, there has been heightened interest in the QT interval, a crucial indicator of ventricular electrical activity. Mendelian randomization (MR) is used here to investigate the genetic causation between QT interval alterations and COVID-19. Genetic proxies representing three COVID-19 phenotypes—severe, hospitalized, and COVID-19—were identified in over 1,000,000 individuals of European ancestry. Univariate two-sample MR (TSMR) and multi-exposure-adjusted multivariate MR (MVMR) were used to assess genetic causal associations between COVID-19 and QT intervals in 84,630 UK Biobank participants. The MR-robust adjusted profile score (MR-RAPS) method and radial MR frame were utilized for effective robustness and outlier variant detection, with sensitivity analyses conducted to identify horizontal pleiotropy. For every COVID-19 phenotype, univariate TSMR analysis revealed non-significant causal estimates between COVID-19 and the QT interval [COVID-19: βIVW (95% CI): −0.44 (−1.72, 0.84), P = 0.50; hospitalization: βIVW: 0.12 (−0.57, 0.80), P = 0.74; severe case: βIVW: 0.11 (−0.29, 0.51), P = 0.58]. MR-RAPS and outlier-corrected radial MR analyses further supported this null causal estimation. In confounder-adjusted MVMR analysis, this nonsignificant causality was independent of body mass index (BMI), smoking, and alcohol consumption [βBMI+Alcohol+Smoking (95% CI): −0.77 (−2.44, 0.91), P = 0.37]. Sensitivity analyses did not detect any evidence of bias from horizontal pleiotropy, abnormal data distribution, or weak instruments. These findings suggest that COVID-19 does not directly causally prolong the QT interval. Inconsistent findings in observational research may be attributed to residual confounding.