Anthracycline-induced cardiotoxicity remains a major clinical challenge, often progressing to heart failure years after therapy. Conventional cardioprotective agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are widely used to preserve cardiac function; however, their effectiveness is limited by their inability to comprehensively address the complex, multifactorial pathophysiology of anthracycline-induced cardiotoxicity. This underscores the critical need for more effective and mechanism-based cardioprotective strategies that directly target the underlying molecular mechanisms, particularly oxidative stress and mitochondrial dysfunction. In recent years, the apelin–APJ signalling axis has attracted increasing attention as a potential therapeutic target in cardiovascular diseases owing to its multifaceted biological actions, including positive inotropy, vasodilation, anti-inflammatory, anti-fibrotic, anti-apoptotic, antioxidant, and pro-angiogenic effects. These pleiotropic actions are primarily mediated through the activation of key signalling pathways such as phosphoinositide 3-kinase/protein kinase B, extracellular signal-regulated kinases 1/2, and AMP-activated protein kinase. Given that these signalling cascades are disrupted during anthracycline-induced cardiotoxicity, pharmacological activation of the apelin–APJ axis may represent a promising avenue to mitigate anthracycline-associated cardiac injury with greater efficacy than conventional therapies. While native apelin isoforms (apelin-12, -13, -17, and [Pyr¹]apelin-13) are limited by their short half-lives, chemically modified analogues such as LIT01-196 and apelin-17(A2) exhibit enhanced stability and efficacy, with demonstrated cardioprotective effects in preclinical cardiovascular models and patients with chronic heart failure. However, their therapeutic potential in anthracycline-induced cardiotoxicity remains largely unexplored. This review highlights its promise as a novel cardioprotective strategy for mitigating anthracycline-induced cardiotoxicity. Graphical Abstract Cardiovascular risk factors and anthracycline (e.g. doxorubicin) exposure trigger shared pathological alterations, ultimately leading to cardiovascular disease and cardiomyopathy, respectively. Activation of the apelin–APJ signalling axis by native apelin peptides or modified apelin analogues engages pro-survival pathways, thereby alleviating these pathological processes. While apelin–APJ signalling confers cardioprotection in cardiovascular diseases, its role in anthracycline-induced cardiotoxicity remains a critical knowledge gap requiring mechanistic and translational investigations. CVD: Cardiovascular disease. Red arrows/lines indicate pathological processes, blue arrows/lines indicate protective effects, and blunt T-bar (⊣) indicates blockade/inhibition. Upward arrows indicate increased activity or pathological alteration.

Targeting the Apelin–APJ Axis: A Promising Strategy to Mitigate Anthracycline-Induced Cardiotoxicity

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发表日期：

2026年4月17日

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Varsha G. Desai

摘要

Anthracycline-induced cardiotoxicity remains a major clinical challenge, often progressing to heart failure years after therapy. Conventional cardioprotective agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are widely used to preserve cardiac function; however, their effectiveness is limited by their inability to comprehensively address the complex, multifactorial pathophysiology of anthracycline-induced cardiotoxicity. This underscores the critical need for more effective and mechanism-based cardioprotective strategies that directly target the underlying molecular mechanisms, particularly oxidative stress and mitochondrial dysfunction. In recent years, the apelin–APJ signalling axis has attracted increasing attention as a potential therapeutic target in cardiovascular diseases owing to its multifaceted biological actions, including positive inotropy, vasodilation, anti-inflammatory, anti-fibrotic, anti-apoptotic, antioxidant, and pro-angiogenic effects. These pleiotropic actions are primarily mediated through the activation of key signalling pathways such as phosphoinositide 3-kinase/protein kinase B, extracellular signal-regulated kinases 1/2, and AMP-activated protein kinase. Given that these signalling cascades are disrupted during anthracycline-induced cardiotoxicity, pharmacological activation of the apelin–APJ axis may represent a promising avenue to mitigate anthracycline-associated cardiac injury with greater efficacy than conventional therapies. While native apelin isoforms (apelin-12, -13, -17, and [Pyr¹]apelin-13) are limited by their short half-lives, chemically modified analogues such as LIT01-196 and apelin-17(A2) exhibit enhanced stability and efficacy, with demonstrated cardioprotective effects in preclinical cardiovascular models and patients with chronic heart failure. However, their therapeutic potential in anthracycline-induced cardiotoxicity remains largely unexplored. This review highlights its promise as a novel cardioprotective strategy for mitigating anthracycline-induced cardiotoxicity.

Graphical Abstract

Cardiovascular risk factors and anthracycline (e.g. doxorubicin) exposure trigger shared pathological alterations, ultimately leading to cardiovascular disease and cardiomyopathy, respectively. Activation of the apelin–APJ signalling axis by native apelin peptides or modified apelin analogues engages pro-survival pathways, thereby alleviating these pathological processes. While apelin–APJ signalling confers cardioprotection in cardiovascular diseases, its role in anthracycline-induced cardiotoxicity remains a critical knowledge gap requiring mechanistic and translational investigations. CVD: Cardiovascular disease. Red arrows/lines indicate pathological processes, blue arrows/lines indicate protective effects, and blunt T-bar (⊣) indicates blockade/inhibition. Upward arrows indicate increased activity or pathological alteration.