Abdominal aortic aneurysm (AAA) is an asymptomatic disease of high mortality rate (65% to 85%) if rupture occurs. Surgical repair is the only effective treatment, but limited to eligible patients (about 10% of total). No effective pharmacological approach has been identified to limit AAA progression and rupture. Male sex is an important risk factor for AAA, with about 4-6:1 male to female prevalence ratio. The reasons for this sex disparity are unknown, but the delayed onset of AAA in women suggests that estrogen and its receptors (ERs) may play a role in reducing the prevalence of AAA. Administration of estrogen has protective effects in AAA animal models through reduction of pro-inflammatory mediators and the proteolytic pathway. However, long- term estrogen therapy cannot be widely applied to treat AAA patients due to undesirable side-effects. Human genetic studies uncovered that Kruppel-like factor 14 (KLF14) is robustly associated with chronic metabolic diseases with a sex difference. We previously reported the biological function of KLF14 and its activator, perhexiline, clinically used to treat angina and heart failure, in lipid metabolism and demonstrate the strong anti-inflammatory effect of KLF14. Our preliminary data described herein established that macrophage- selective Klf14 knockout mice showed significantly increased AAA incidence rates in females, comparable to those in males, suggesting impaired protective effects of estrogen/ERα/β pathway. Besides the inhibitory effects of KLF14 on the inflammatory response and MMP-9 activity, we further found that estrogen upregulates the expression of KLF14 while KLF14, in turn, is a critical transcription factor upregulating the expression of ERα/β in macrophages, uncovering a feedforward loop that may contribute to the observed sex disparity. Perhexiline increased the levels of ERα/β in a KLF14-dependent manner. A cholesterol metabolite, 24- hydroxycholesterol (24HC), functioned as an endogenous ERα/β agonistic molecule and enhanced the anti- inflammatory effect of perhexiline in macrophages. Most importantly, administration of perhexiline significantly reduced AAA dissection/rupture and increased survival rate in male mice. Based on our preliminary findings, the proposed project will test the central hypothesis that KLF14 protects against AAA development/dissection /rupture by suppressing inflammation and enhancing ERα/β-dependent protective roles in macrophages. The specific aims will 1) define that macrophage KLF14 is an important regulator of sex differences in AAA mouse models; 2) determine how KLF14 regulates the estrogen/ERs pathway which contributes to sex-dimorphic protective effects on AAA; and 3) determine that activation of KLF14 inhibits development/dissection/rupture in AAA mouse models. Based on the sex-specific functions of KLF14 in AAA, this mechanistic research will establish KLF14 as a novel therapeutic target and will set a solid foundation towards clinical utilization of...