ObjectiveTo investigate how genetic variations in obesity-related genes (FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1) impact the NF-κB signaling pathway, exploring mechanisms of NF-κB activation, downstream inflammatory responses, and their role in cardiovascular disease (CVD) development in the context of obesity.BackgroundObesity is a leading contributor to chronic diseases, including CVD, driven in part by chronic low-grade inflammation. The NF-κB signaling pathway, a central regulator of inflammatory responses, is implicated in the pathophysiology of obesity and CVD. Genetic variations in obesity-related genes may modulate NF-κB activation and its downstream effects, exacerbating inflammation and cardiovascular risks. Understanding these mechanisms can inform therapeutic strategies to mitigate inflammation and improve health outcomes in individuals with obesity.MethodsA systematic review of the literature was conducted using PUBMED, MEDLINE, and Google Scholar, focusing on genetic variations in the obesity-related genes FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1. Studies examining the effects of these variations on NF-κB activation, inflammatory pathways, and CVD development were included. The search was performed with no date restrictions and followed PRISMA guidelines. Articles were screened for relevance, methodological rigor, and insights into the interplay between genetic factors, inflammation, and cardiovascular pathology. Data extraction focused on key findings linking gene variants to NF-κB signaling and their downstream effects.ResultsGenetic variations in FTO, MC4R, LEP, LEPR, and SH2B1 were found to disrupt insulin and leptin signaling, resulting in enhanced NF-κB activation and chronic inflammation. Variants in PPARG and UCP1 increased oxidative stress, further amplifying NF-κB signaling. These changes promoted endothelial dysfunction, atherosclerosis, and heightened CVD risk. Interactions between these genetic factors created a pro-inflammatory state, exacerbating cardiovascular complications in obese individuals.ConclusionThis study underscores the critical role of genetic variations in obesity-related genes in modulating NF-κB signaling, driving chronic inflammation, and increasing CVD risk. Targeting these pathways may provide therapeutic opportunities to reduce inflammation and improve cardiovascular health in obese populations.