Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disorder with poorly understood pathogenesis. We conducted Mendelian randomization (MR) analyses integrating cardiovascular factors, gut microbiota (GM) composition, and immune cell phenotypes with transcriptomic profiling to establish causal relationships with ALS susceptibility. MR revealed causal associations between elevated low-density lipoprotein cholesterol, apolipoprotein B, systolic blood pressure, and increased ALS risk. GM analysis identified protective Alistipes species effects and detrimental Bacteroides associations. Multiple immune cell subsets demonstrated significant disease associations, particularly CD3 + T cell populations and CD62L+ monocytes. Colocalization studies identified 53 genes with shared genetic architecture, enabling differential expression analysis across datasets. Predictive modeling developed a five-gene biomarker panel achieving 96% training accuracy and 93% external validation. Quantitative PCR confirmed differential expression patterns for biomarkers in patient cohorts. This multi-omics investigation establishes ALS as a complex disorder with actionable cardiovascular and microbiome therapeutic targets, providing applications for risk stratification and prevention.

Neonatal necrotizing enterocolitis (NEC) is an intestinal disease that occurs in the neonatal period. The purpose of this study was to investigate the role of 5′‐aminolevulinate synthase 2 (ALAS2) in NEC‐induced intestinal injury. In a neonatal mouse, NEC model was induced by high‐osmolarity formula and hypoxia‐cold stress, and ALAS2 expression was significantly downregulated in ileal tissues ( p < 0.01), coinciding with elevated oxidative stress (increased Fe ²⁺ /malondialdehyde [MDA] and decreased superoxide dismutase [SOD]), inflammation (increased TNF‐α/interferon‐gamma [IFN‐γ]), and ferroptosis activation (increased acyl‐CoA synthetase long‐chain family member 4 [ACSL4] and decreased ferritin heavy chain 1 [FTH1] with mitochondrial shrinkage). In vitro, tumor necrosis factor‐alpha (TNF‐α)/IFN‐γ‐treated intestinal epithelial cell (IEC) exhibited progressive ALAS2 suppression and increased necrosis. Crucially, lentivirus‐mediated ALAS2 overexpression reversed these effects, reducing cell necrosis by 22% while suppressing ferroptosis markers (Fe ²⁺ accumulation, lipid reactive oxygen species [ROS], and mitochondrial depolarization) and oxidative damage (decreased MDA and restored glutathione [GSH]/catalase [CAT]/SOD). Untargeted metabolomics further revealed ALAS2‐mediated modulation of nutrient metabolism and redox pathways. Collectively, ALAS2 ameliorates NEC by blocking oxidative stress‐driven ferroptosis in IECs, proposing a novel therapeutic target.

Hirschsprung’s disease (HSCR) is a congenital disorder characterized by intestinal aganglionosis. Despite evidence linking gut microbiota and immune