Pre-obesity, as a significant risk factor for the progression of metabolic syndrome (MS), has become a prevalent public health threat globally. In this three-year longitudinal study of pre-obese women at baseline, the goal was to clarify the female-specific bidirectional relationship between the risk of MS and blood alanine aminotransferase. In this manuscript, the MS score was determined using the following equation: MS score = 2*waist/height + fasting glucose/5.6 + TG/1.7 + SBP/130—HDL/1.02 for men and 1.28 for women, which is highly related to the risk of MS. With 2,338 participants, a hierarchical nonlinear model with random effects was utilized to analyze the temporal trends of serum characteristics from 2017 to 2019. A bivariate cross-lagged panel model (CLPM) was employed to estimate the structural relations of frequently measured variables at three different time points to determine the directionality of the relationship between the risk of MS and serum characteristics. MassARRAY Analyzer 4 platforms were used to evaluate and genotype candidate SNPs. In this study, the MS score only rose with age in females; it was positively correlated with serum alanine aminotransferase (ALT) in females; the CLPM revealed that the MS score in 2017 predicted ALT in 2018 (β = 0.066,p< 0.001); and ALT in 2018 predicted an MS score in 2019 (β = 0.037,p< 0.050); both relationships were seen in females. Additionally, the MS score in elderly females with NAFLD was related to the rs295 in the lipoprotein lipase (LPL) gene (p= 0.042). Our work showed that there may be female-specific causal correlations between elevated ALT and risk of MS and that the polymorphism rs295 inLPLmay serve as a marker for the prognosis of MS. The genetic roles of rs295 in theLPLgene in the onset of MS and the development of ALT in the elderly Chinese Han population are thus provided by this, offering one potential mechanism.