Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026018
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.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025213
Myocardial infarction (MI) causes irreversible cardiomyocyte loss, creating a need for cardiac repair therapies. The role of cell division cycle 5-like (CDC5L), a cell cycle regulator, in cardiac repair is unknown. This study aims to define the role of CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing its impact on cardiomyocyte proliferation and apoptosis and to determine the mechanism involving the FGF10-YAP axis. We model cardiac injury using in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and in vivo I/R in adult mice. To investigate CDC5L function, we modulate its expression via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU+, Ki67+, pH3+), apoptosis (TUNEL staining, Bax/Bcl-2 ratio), and cardiac function (echocardiography) are assessed. Through transcriptomic screening, we identify CDC5L downstream targets and validate their functional roles using FGF10 knockdown rescue assays. We find that CDC5L is upregulated in the post-I/R murine myocardium. Its overexpression enhances cardiomyocyte proliferation, preserves cardiac function, reduces apoptosis, and diminishes infarct size. Transcriptomic analysis identifies FGF10 as a key downstream effector, and we confirm that CDC5L upregulates FGF10 expression. Notably, FGF10 knockdown reverses the proliferative and anti-apoptotic effects of CDC5L. Moreover, the CDC5L-mediated reduction in YAP phosphorylation is also dependent on FGF10, as this effect is abolished upon FGF10 knockdown. In conclusion, CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026018
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.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025213
Myocardial infarction (MI) causes irreversible cardiomyocyte loss, and current reperfusion therapies fail to regenerate necrotic myocardium. Cell division cycle 5-like (CDC5L), a cell cycle regulator, has an undefined role in cardiac repair. This study investigates CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing cardiomyocyte proliferation and apoptosis, and delineates the FGF10-YAP mechanism. In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and in vivo I/R in adult mice were employed. CDC5L was modulated via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU+, Ki67+, pH3+), apoptosis (TUNEL, Bax/Bcl-2 ratio), and cardiac function (echocardiography) were quantified. Transcriptomic screening identified downstream targets, validated by FGF10 knockdown rescue. CDC5L was upregulated in post-I/R murine myocardium. Overexpression enhanced cardiomyocyte proliferation, preserved cardiac function, reduced apoptosis, and diminished infarct size. FGF10 was identified as a key downstream effector; CDC5L upregulated FGF10 expression. FGF10 knockdown reversed the proliferative and anti-apoptotic effects of CDC5L. The CDC5L-mediated reduction in YAP phosphorylation was abolished upon FGF10 knockdown. CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.