Genetic Insights Into the Central Role of Serine β‐Lactamase‐Like Protein in Lipid Metabolism, Metabolic Syndrome, and Chronic Kidney Disease

ABSTRACT Serine β‐lactamase‐like protein (LACTB), a mitochondrial protease, has incompletely characterized roles in metabolic pathways. We employed Mendelian randomization to investigate LACTB's causal relationships with lipid metabolism, metabolic syndrome (MetS), and chronic kidney disease (CKD). We performed a comprehensive Mendelian randomization (MR) analysis using genome‐wide association study summary statistics. Cis‐expression quantitative trait loci from the eQTLGen consortium identified genetic instruments for LACTB. Two‐sample MR approaches, including inverse variance weighted, MR‐Egger, and weighted median methods, were applied. The cisMR‐conditional maximum likelihood (cisMR‐cML) method validated LACTB‐related causal associations. GTEx Portal data independently replicated the LACTB‐CKD relationship. LACTB exhibited significant negative causal effects on metabolic syndrome (95% CI: 0.91–0.99, p = 0.02) and chronic kidney disease (95% CI: 0.83–0.97, p = 0.009). cisMR‐cML validation confirmed significant causal associations between LACTB and lipid profiles after Bonferroni correction. Metabolic syndrome demonstrated a robust positive causal effect on CKD (95% CI: 1.15–1.42, p = 8.45 × 10 −6 ), with high‐density lipoprotein showing a significant negative causal relationship with CKD (95% CI: 0.89–0.97, p = 0.0009). Mediation analysis revealed metabolic syndrome mediated 11.8% of the total effect between LACTB and CKD (mediation effect: −0.01, 95% CI: −0.024 to −0.0003). Our study elucidates LACTB's critical role in metabolic regulation, identifying a potential therapeutic target for preventing chronic kidney disease progression. By delineating complex interactions between LACTB, lipid metabolism, metabolic syndrome, and kidney function, we provide novel insights for precision medicine in metabolic and renal health.