Activation of SIRT1 by Hydroxysafflor Yellow A Attenuates Chronic Unpredictable Mild Stress‐Induced Microglia Activation and Iron Death in Depressed Rats

ABSTRACT Background Hydroxysafflor yellow A (HSYA), the main active ingredient in safflower, possesses antioxidant and anti‐inflammatory activities. We confirmed in our previous study that HSYA exerts antidepressant effects, but further investigation is needed to uncover the exact mechanism. Herein, we aimed to explore the antidepressant effects of HSYA based on microglial activation and ferroptosis studies. Methods The chronic unpredictable mild stress (CUMS) procedure was used to establish a depression model in rats. Behavioral tests were conducted on rats after HSYA administration. Iba‐1 immunostaining was used to determine the activation of microglia in the hippocampus. We examined the iron ion level using a colorimetric method. Assayed by western blot for protein expression. Results Rats receiving HSYA showed enhanced spatial learning and memory abilities, as well as improvements in depression‐like behaviors. HSYA administration reduced Iba‐1 expression in CUMS rats’ hippocampus, indicating that HSYA suppressed microglial activation. HSYA inhibited CUMS‐induced Fe 2+ concentration and promoted ferroptosis‐related protein GPX4 and SLC7A11 expression. HSYA treatment also elevated SIRT1 and Nrf2 protein levels, while p‐p65 protein levels decreased in the hippocampus of CUMS rats. Conclusion HSYA exerts an antidepressant‐like effect by inhibiting microglia activation in the hippocampus and inducing SIRT1/Nrf2/NF‐kB signaling.