〔Abstract〕 Objective To investigate the effects of lectin-like oxidized low-density lipoprotein receptor-1（LOX-1） gene G501C on brain structure and cognitive function in patients with white matter hyperintensities（WMH）. Meth ⁃ ods A total of 118 patients with WMH were enrolled. All participants underwent T 1-weighted and T2-fluid- attenuated inversion recovery（T2-FLAIR）MRI to assess gray matter structure and WMH burden，and completed the mini-mental state examination（MMSE）and Montreal cognitive assessment（MoCA）. Partial correlation and mediation analyses were performed to explore the impact of LOX-1 polymorphism on cognitive function. Results Participants were divided into GG+GC group（n = 35）and CC group（n = 83）. The GG+GC group showed lower MMSE and MoCA scores（MMSE：P=0. 003 ；MOCA：P=0. 015）， as well as greater WMH burden（all P< 0. 001），compared with the CC group. Voxel-based morphometry（VBM）analysis revealed reduced left thalamic volume in the GG+GC group，which was correlated with cognitive scores（all P<0. 05）. Subregional thalamic analysis further showed volume reductions in the lateral，ventral，medial，and pulvinar thalamic regions（all P< 0. 05）in the GG+GC group，all positively associated with cognitive performance（all P<0. 05）. Mediation analy_ ses indicated that volumes of the medial and pulvinar thalamic regions mediated the association between genotype and cognitive function（MMSE，MoCA）， and that WMH volume mediated the effect on MoCA scores. Conclu ⁃ sion The LOX-1 G501C polymorphism may indirectly affect cognitive function by influencing specific thalamic subregional volumes and white matter damage，suggesting a potential mediating role of thalamic structures between genetic background and cognitive impairment.