Blocking a Single Enzyme Rescues Heart Cells From Chemotherapy Damage

Doxorubicin (DOX) remains one of oncology's most effective chemotherapeutics, but its dose-limiting cardiotoxicity restricts use and harms long-term survivors. NAD+ depletion is a well-established driver of DOX-induced cardiomyopathy (DIC), yet almost all cardioprotective strategies have focused on the salvage pathway (NR, NMN supplementation) or NAD+-consuming enzyme inhibition. This study is the first to systematically investigate the de novo NAD+ biosynthesis route — the kynurenine pathway (KP) — as a protective mechanism specifically in DIC.

Using genetic and pharmacological tools in murine models, the researchers show that IDO1, the enzyme initiating tryptophan catabolism into kynurenine, is cardioprotective. Global IDO1 knockout (IDO1KO) mice and cardiac-specific IDO1 knockdown mice (via AAV9-shRNA) both showed significantly worse cardiac function, greater fibrosis, higher ROS levels, and depleted NAD+ when treated with cumulative DOX (15 mg/kg over 6 weeks). These data firmly establish that the endogenous KP protects cardiomyocytes against DOX stress.

Mechanistically, DOX was found to activate the STING/IFN-γ/p-AMPK signaling axis, which simultaneously upregulates ACMSD — a branch-point enzyme that diverts the intermediate α-amino-β-carboxymuconate-ε-semialdehyde (ACMS) away from quinolinic acid (QA) and toward the TCA cycle — and suppresses QPRT, which converts QA into the NAD+ precursor nicotinic acid mononucleotide (NAMN). The net result is a dramatic reduction in QA and NAD+ levels in cardiomyocytes, impairing the SIRT1/Nrf2/SOD2 antioxidant axis and energy metabolism. Targeted LC-MS/MS metabolomics of heart tissue confirmed depleted KP intermediates including tryptophan, 3-HAA, and QA following DOX treatment.

Pharmacological inhibition of ACMSD using TES-1025 (15 mg/kg i.p.) reversed this metabolic block, restoring QA flux toward NAD+ synthesis. TES-1025-treated DIC mice showed improved left ventricular ejection fraction (LVEF) and fractional shortening, reduced cardiac fibrosis on Masson trichrome staining, lower ROS levels (DHE staining), restored ATP production, and normalized mitochondrial respiration (Seahorse OCR assays). Isotope tracing with 13C-tryptophan in primary cardiomyocytes confirmed that ACMSD inhibition increased 13C-labeled QA and downstream NAD+ metabolites in a time-dependent manner. Importantly, TES-1025 did not rescue MCF7 breast cancer cells from DOX-induced death, preserving chemotherapeutic efficacy — a critical safety finding that distinguishes this approach from NR/NMN supplementation, which carries tumor-promoting risk.

These findings position ACMSD as a druggable metabolic switch in the heart and open a novel therapeutic avenue for preventing chemotherapy-associated cardiomyopathy without compromising anti-cancer activity.