Cardiac PTN-SIRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signaling

Abstract

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent for malignancies, yet its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to progressive left ventricular dysfunction and heart failure. Pleiotrophin (PTN), a heparin-binding growth factor with diverse physiological functions, regulates glucose and lipid metabolism and promotes oxidative energy pathways. However, whether PTN exerts protective effects against DOX-induced cardiotoxicity (DIC) remains unclear. In this study, we establish cellular and animal models of DIC. DOX administration induces pronounced myocardial injury in both models, characterized by impaired ventricular contractility, increased fibrotic remodeling, and reduced cell viability. Concurrently, PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment. Overexpression of PTN substantially alleviates these pathological changes. In vitro, PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability. In vivo, PTN improves mitochondrial ultrastructure, decreases cardiomyocyte apoptosis, and enhances cardiac function. Mechanistically, PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172, triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity. In conclusion, the PTN-SIRT1 axis protects against DIC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway, highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.

1. Introduction

Doxorubicin (DOX) is an anthracycline utilized for chemotherapeutic treatment of a variety of cancers, including breast cancer and leukemia [1–4]. Despite its potent antitumor properties, DOX’s clinical use is frequently limited by its cardiotoxic profile, which manifests as progressive left ventricular dysfunction, arrhythmogenesis, and ultimately, heart failure [5–7]. The underlying pathophysiology of DOX-induced cardiotoxicity (DIC) remains incompletely elucidated, although multiple pathways have been implicated, including the generation of excess reactive oxygen species (ROS), damage to DNA, inflammation, disruption of mitochondrial energetics, and apoptotic signaling cascades [8–12]. Currently, therapeutic interventions for DIC are largely palliative, underscoring the pressing need to identify novel molecular targets and mechanisms that can effectively prevent or reverse cardiac injury induced by DOX.

Among the key contributors to DIC is mitochondrial dysfunction within cardiomyocytes [13,14]. The accumulation of DOX in mitochondria impairs their structural integrity and bioenergetic function, in part by disrupting electron transport chain (ETC) complexes I, II, and IV and binding irreversibly to cardiolipin on the inner mitochondrial membrane [15–19]. These alterations compromise ATP production, exacerbate oxidative stress, and amplify myocardial injury, creating a cascade that accelerates the onset of heart failure [20,21]. As such, reducing mitochondrial oxidative stress and preserving mitochondrial function has emerged as a promising strategy in the quest to mitigate DIC.