Ablation of ACSS2 drives alteration to cardiac and hepatic proteomic landscapes in a tissue- and sex-specific manner.

ACSS2 catalyzes the conversion of acetate into acetyl-CoA, linking nutrient availability to cellular processes such as lipid biosynthesis, energy production, and epigenetic regulation. Although ACSS2 has been studied under metabolically stressful conditions, its basal sex- and tissue-specific functions remain poorly defined. Here, we employed comprehensive proteomic characterization of the impact of global ACSS2 ablation in the liver and heart of adult male and female mice. Over 6000 proteins were identified per tissue, providing deep proteomic coverage. Despite the liver exhibiting greater baseline abundance of ACSS2, the most extensive remodeling occurred in the heart. Both tissues displayed marked sex differences, with males showing greater overall proteomic shifts, and minimal overlap in differentially abundant proteins occurring between males and females. Shared alterations across tissues converged on metabolic and immune regulation, whereas sex-specific changes implicated distinct structural and signaling pathways. Comparatively modest hepatic changes may reflect compensatory processes in the liver, in contrast to the strong inhibitory remodeling observed in the heart. These findings reveal a previously unrecognized degree of tissue- and sex-specificity in regulation by ACSS2, while also highlighting the importance of including female mice in proteomic studies, as male only approaches may overlook key sex-dependent adaptations.