〔Abstract〕 Abstract Objective To investigate the mechanism of prostaglandin E synthase 3 (PTGES3) / heat shock protein 90 (HSP90) in the medial prefrontal cortex regulating obesity-related cognitive dysfunction . Methods This study consisted of clinical trials and animal experiments . In part one , obese patients scheduled for bariatric surgery , and healthy adults matching gender and age were recruited at the same time to reach 10 cases in each group . The cogni- tive level was assessed with trail making test part A (TMT-A) and victoria stroop tests (VST) . Four-dimensional data-independent acquisition (4D-DIA) was used to screen the proteome changes in peripheral blood . In part two ,forty SPF healthy male C57BL/6J mice were randomly divided into four groups : normal diet group ( ND group) , high fat diet induced obesity group (DIO group) , DIO supplemented with the control virus group (DIO + Scramble group) and DIO supplemented with the interfering virus group (DIO + shPTGES3 group) . The Morris water maze test was conducted to evaluate the cognitive behavior changes of the four groups of mice . The immunofluorescence staining was performed to detect the expression of PTGES3 and HSP90 in the medial prefrontal cortex and the acti- vation of ionized calcium binding adapter molecule 1 (IBA1)-labeled microglia. Results In the case-control stud- y , the cognitive function of obese patients significantly decreased , and the expression of PTGES3 in peripheral blood significantly increased , while the level of PTGES3 was negatively correlated with cognitive function . In ani- mal experiments , compared with ND group , DIO group had significantly prolonged time reaching the target plat- form , otherwise , the residence time in the target quadrant was shortened in the Morris water maze test. Simultane- ously , there were significant increase in the expression of PTGES3 and HSP90 , and the activation of IBA1 in the medial prefrontal cortex. Compared with DIO + Scramble group , mice in the DIO + shPTGES3 group spent less time reaching the target platform , and stayed longer in the target quadrant. The expression and co-localization levels of PTGES3 and HSP90 in medial prefrontal cortex significantly decreased . The activation level of microglia cells was also attenuated by PTGES3 interference . Conclusion Obesity-related cognitive dysfunction may be attributed to PTGES3/HSP90 in the medial prefrontal cortex by mediating neural inflammation .