Abstract Body: Oxalate is an end-product of metabolism known to cause primary hyperoxalurias (PHs). PHs are metabolic disorders characterized by hepatic overproduction of oxalate, leading to severe renal and cardiac complications from early life. Recent evidence has unveiled oxalate’s pivotal role in exacerbating metabolic dysfunction-associated steatohepatitis (MASH), increasing steatosis, inflammation and fibrosis. This pathological progression appears to extend further, linking oxalate dysregulation to atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in MASH patients. To address the high prevalence and health burden of MASH and ASCVD, we propose repurposing oxalate-lowering strategies initially developed for PHs. Currently, two FDA-approved drugs, Lumasiran and Nedosiran, target this pathway by silencing the expression of Glycolate Oxidase (GO) and Lactic Dehydrogenase (LDH), respectively. However, their prohibitive cost and restrictive administration route (in-hospital injections) limit their applicability for the large population of patients with cardiometabolic diseases. To overcome these barriers, our interdisciplinary team has developed small-molecule dual inhibitors of GO and LDH designed for oral bioavailability and cost-effective synthesis. To date, our lead candidate MDMG-935P, demonstrated IC₅₀ = 17.3 µM, K_i= 24.7 µM on GO and IC₅₀ =2.0 µM, K_i= 10.5 µM on LDH on in vitro enzymatic assays. Notably, MDMG-935P reduces oxalate by 50% on in vivo models of PH and potently lowers diet-induced MASH and hepatic fibrosis. Herein, we report a series of novel dual GO-LDH inhibitors with IC₅₀ and K_i in the nanomolar range, their in vitro evaluation in primary hepatocytes, as well as the in vivo outcomes of the ongoing long-term study in MASH and ASCVD model. This work offers a promising therapeutic strategy for addressing the interconnected metabolic and cardiovascular pathologies driven by oxalate dysregulation.