# Metabolomic Profiling of Tyrosine Kinase Inhibitor-Induced Endothelial Dysfunction and Cardiovascular Toxicity

## TL;DR

This paper explores how tyrosine kinase inhibitors used in cancer treatment cause heart problems by analyzing metabolic changes and proposes ways to detect and prevent these issues early.

## Contribution

The study identifies novel metabolomic signatures of TKI-induced cardiovascular toxicity and proposes metabolomics-guided strategies for cardioprotection.

## Key findings

- Metabolomic profiling reveals three key axes of TKI-induced cardiovascular toxicity: mitochondrial dysfunction, endothelial nitric oxide disruption, and inflammation.
- Rodent models of sunitinib and sorafenib show metabolomic signatures matching human data and demonstrate heart injury and dysfunction.
- L-carnitine and AMPK signaling restoration in preclinical models supports metabolomics-guided cardioprotection.

## Abstract

Background: Tyrosine kinase inhibitors (TKIs) have transformed cancer therapy; however, they are associated with cardiovascular toxicity. Metabolomics provides a comprehensive framework for identifying early biochemical disruptions that precede clinical manifestations and for formulating mechanism-based intervention strategies. Methods: We conducted a narrative synthesis of published preclinical and translational studies on TKI cardiotoxicity, focusing on untargeted and targeted metabolomic findings and complementary proteomic and transcriptomic data. Functional validation was performed using rodent and cellular models. Mechanistic themes were identified, and implications for biomarker panels, multi-omic integration, and metabolomics-guided interventions were proposed. Conclusions: Metabolomic analyses of various TKIs identified convergent signatures along three interconnected axes: (1) mitochondrial bioenergetic dysfunction characterized by impaired long-chain fatty acid oxidation and adenylate depletion; (2) disruption of endothelial nitric oxide signaling with redox imbalance, including increased nitrotyrosine, Nox activation, and eNOS uncoupling; and (3) an inflammatory metabolic profile marked by elevated branched-chain and aromatic amino acids, creatine, and osmolytes. Rodent models of sunitinib and sorafenib replicate these signatures and demonstrate histological injury, contractile dysfunction, and fibrosis. Preclinical intervention data, particularly restoration of myocardial carnitine, AMPK signaling, and fatty acid oxidation by L-carnitine, provide proof of concept for metabolomics-guided cardioprotection. Metabolomics can identify mechanistic biomarkers that facilitate the early detection, risk stratification, and targeted prevention of TKI-induced cardiovascular injury. Translation into precision cardio-oncology requires prospective validation, standardized assays, and biomarker-driven interventional trials.