What question did this study set out to answer?

This study aims to explore the role of NINJ1 in doxorubicin-induced cardiotoxicity and its potential as a therapeutic target.

June 24, 2026

NINJ1 Aggravates Doxorubicin-Induced Cardiotoxicity by Suppressing AMPK-Mediated HIF-1α Deubiquitination

Resultado clave

NINJ1 promotes doxorubicin-induced cardiotoxicity by destabilizing HIF-1α via AMPK inhibition, and its targeted inhibition attenuates cardiac injury while preserving anticancer efficacy.

Puntos clave

This study aims to explore the role of NINJ1 in doxorubicin-induced cardiotoxicity and its potential as a therapeutic target.
Utilized genetic and pharmacologic methods to manipulate NINJ1 levels in murine models.
Conducted RNA sequencing and pathway enrichment analyses to elucidate molecular mechanisms.
Applied pharmacologic inhibition of NINJ1 to assess cardiac protection in vivo and in vitro.
NINJ1 is significantly upregulated in doxorubicin-treated cardiomyocytes.
Cardiomyocyte-specific deletion of NINJ1 reduced oxidative stress and cardiac dysfunction, while overexpression worsened injury.
Pharmacologic inhibition of NINJ1 mitigated cardiac injury without affecting doxorubicin's anticancer effects.

PICO estructurado

Does NINJ1 inhibition prevent doxorubicin-induced cardiotoxicity in murine models?

Población

Murine hearts and cardiomyocytes treated with doxorubicin (DOX)

Intervención

Genetic deletion/overexpression of NINJ1 and pharmacologic inhibition with phenyl-β-D-glucopyranoside

Comparador

Control/wild-type models treated with doxorubicin

Resultado

Cardiac dysfunction, oxidative stress, and apoptosissurrogate

NINJ1 inhibition protects against doxorubicin-induced cardiotoxicity by stabilizing HIF-1α via AMPK activation, offering a potential cardioprotective strategy during anthracycline chemotherapy.

Resultado numérico

Tasa de eventos absoluta: 0% vs 0%

Resumen

Aims: Doxorubicin (DOX) remains a cornerstone of cancer therapy but is limited by dose-dependent cardiotoxicity with inadequate protective strategies. Nerve injury-induced protein 1 (NINJ1), a regulator of inflammation and cell death, has not been explored in this context. We sought to define the role of NINJ1 in DOX-induced cardiotoxicity and evaluate its translational potential. Results: Using complementary genetic, pharmacologic, and transcriptomic approaches, we demonstrate that NINJ1 is markedly upregulated in DOX-treated murine hearts and cardiomyocytes. Cardiomyocyte-specific NINJ1 deletion confers robust protection against cardiac dysfunction, oxidative stress, and apoptosis, whereas NINJ1 overexpression exacerbates injury. Mechanistically, NINJ1 suppresses AMP-activated protein kinase (AMPK) activation, promoting ubiquitin-mediated degradation of hypoxia-inducible factor-1α (HIF-1α), thereby impairing antioxidant gene programs. Multilevel evidence, including RNA sequencing, pathway enrichment, and gain- and loss-of-function models, establishes the NINJ1-AMPK-HIF-1α axis as a central regulator of redox homeostasis. Pharmacologic inhibition of NINJ1 with phenyl-β-D-glucopyranoside attenuates cardiac injury in vivo and in vitro without compromising DOX antitumor efficacy, supporting pathway specificity and therapeutic feasibility. Innovation: This study identifies NINJ1 as a previously unrecognized driver of anthracycline cardiotoxicity and uncovers a novel signaling axis linking membrane injury signaling to metabolic control of HIF-1α stability. Conclusions: NINJ1 promotes DOX-induced cardiotoxicity by destabilizing HIF-1α via AMPK inhibition. Targeting NINJ1 represents a promising cardioprotective strategy. Clinical Significance: Therapeutic inhibition of NINJ1 protects the heart while preserving anticancer efficacy, offering a potential strategy to enhance the safety of anthracycline-based chemotherapy and improve outcomes in cancer patients. Antioxid. Redox Signal. 00, 000–000.

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