Reprogramming of the kynurenine pathway impairs NAD(+) homeostasis and mediates doxorubicin-induced cardiotoxicity in mice.

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 NAD(+) synthesis. 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 NAD(+) levels. 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 NAD(+) redox homeostasis and conferring protection against DIC in murine models.