Reprogramming of the kynurenine pathway impairs NADhomeostasis and mediates doxorubicin-induced cardiotoxicity in mice.

Abstract

Imbalance of Nicotinamide adenine dinucleotide (NAD) homeostasis is a key contributor to various cardiac pathologies, including doxorubicin (DOX)-induced cardiomyopathy (DIC). The kynurenine pathway (KP), initiated by indoleamine 2,3-dioxygenase 1 (IDO1), serves as the primary route for de novo NAD  biosynthesis. While this pathway regulates critical biological processes such as cellular metabolism, inflammatory responses, oxidative stress, and aging, its specific role in DIC remains poorly understood. Here, we reveal a protective function of the KP in DIC by facilitating NADsynthesis. Genetic ablation of IDO1 exacerbates DOX-induced cardiac injury and structural damage in mice. In cardiomyocytes, DOX treatment upregulates α-amino-β-carboxy-muconate-semialdehyde decarboxylase (ACMSD) while downregulating quinolinate phosphoribosyl-transferase (QPRT), thereby reducing levels of the intermediate metabolite quinolinic acid (QA) and NADlevels. These effects can be pharmacologically reversed by TES-1025, an ACMSD inhibitor that enhances QPRT activity and potentiates the cardioprotective effects of the KP pathway against DIC. Mechanistically, we show that DOX modulates the STING/interferon γ/5'-AMP-activated protein kinase (p-AMPK) signaling axis to elevate ACMSD and suppress QPRT. Our findings establish a novel therapeutic potential that targets the metabolic switch ACMSD to QPRT, restoring NADredox homeostasis and conferring protection against DIC in murine models.