Autophagy - Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity

Sep 28, 2026

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Entrectinib is a neurotrophic tyrosine receptor kinase (NTRK) inhibitor with clinical benefit for brain metastases, yet it can cause severe cardiotoxicity and lacks effective interventions. A proteomics-based and murine study using cardiomyocyte-specific Atg7 deletion shows that entrectinib activates cardiomyocyte autophagy, then triggers apoptosis and cardiac dysfunction. Mechanistically, entrectinib directly binds HMGB1 at Phe103 to enhance nuclear localization and suppress OTUD5, inhibiting MTORC1 and activating macroautophagy. HMGB1 inhibition, including tanshinone IIA, prevents this cardiotoxicity in vivo and in vitro, supporting safer clinical use.

LanguageEnglish

CategoryHealthcare

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Pages21

Reading Time53 min

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Abstract

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Introduction

AUTOPHAGY 2025, VOL. 21, NO. 12, 3266–3286 [https://doi.org/10.1080/15548627.2025.2576619](https://doi.org/10.1080/15548627.2025.2576619) | RESEARCH PAPER
Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity
Zizheng Gaoa, Jiaqi Zhanga, Huangxi Fua, Shaoyin Zhanga, Jian Chena, Haiyang Zhoua, Xueqin Chenb, Xiaochen Zhangc, Hao Yana, Bo Yanga,d,e, Qiaojun Hea,d, Zhifei Xua, and Peihua Luo a,e
aCollege of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, P. R. China; bDepartment of Thoracic Oncology, Hangzhou Cancer Hospital, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, P. R. China; cDepartment of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China; dSchool of Medicine, Hangzhou City University, Hangzhou, Zhejiang, P. R. China; e Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, P. R. China | | | | --- | --- | --- | | ABSTRACT
Entrectinib stands unparalleled as the sole neurotrophic tyrosine receptor kinase (NTRK) inhibitor that has demonstrated clinical efficacy in treating brain metastases across various cancer types. However, its potential to induce severe cardiotoxicity, compounded by the current lack of effective intervention strategies, poses a substantial risk of treatment failure, underscoring the critical need for in-depth research on the molecular mechanism. Here, we utilized proteomics analysis and a murine model with cardiomyocyte-specific atg7 deletion to reveal that entrectinib activated autophagy in cardiomyocytes, subsequently triggering apoptosis and leading to cardiac dysfunction. Mechanistically, entrectinib directly bound to the HMGB1 protein at the 103rd phenylalanine residue, enhancing its nuclear localization. In the nucleus, HMGB1 suppressed the transcription of the deubiquitinating enzyme OTUD5, a vital regulator of the MTORC1 pathway, which subsequently inhibited the MTORC1 pathway, culminating in the activation of macroautophagy/autophagy. Furthermore, our research demonstrated that HMGB1 inhibition could prevent the cardiotoxicity induced by entrectinib in both in vivo and in vitro models. Specifically, we found that tanshinone IIA could mitigate the cardiotoxic effects of entrectinib by reducing HMGB1 protein levels. Taken together, our findings elucidated the mechanism underlying entrectinib-induced cardiotoxicity, offering a theoretical foundation for the safer clinical application of this targeted therapy. | | ARTICLE HISTORY
Received 4 April 2025 Revised 7 October 2025 Accepted 13 October 2025
KEYWORDS
Autophagy; cardiac dysfunction; cardiotoxicity; entrectinib; HMGB1; MTORC1; tanshinone IIA | | Abbreviations and Acronyms: ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase family; DAPI: 4‘6-diamidino-2-phenylindole; EF: ejection fraction; FS: fractional shortening; GSEA: gene set
enrichment analysis; H&E: hematoxylin and eosin; HW:TL: ratio of heart weight to tibia length; KEGG: Kyoto Encyclopedia of Genes and Genomes; MYH6: myosin heavy polypeptide 6, cardiac muscle, alpha; MYH7: myosin, heavy polypeptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; WGA: wheat germ agglutinin. | | | | Introduction
Adverse cardiovascular events are among the greatest challenges in the management of cancer patients and have promoted the emergence of cardio-oncology, an important cardiovascular subspecialty. In August 2019, the FDA granted approval for entrectinib, a landmark therapy for adults

FAQs

What problem does the study address about entrectinib treatment?

It addresses the risk of severe cardiotoxicity caused by entrectinib, alongside the lack of effective intervention strategies and unclear molecular mechanisms.

How does entrectinib trigger cardiomyocyte autophagy according to the mechanism proposed?

Entrectinib directly binds HMGB1, enhances HMGB1 nuclear localization, and suppresses OTUD5 transcription, which inhibits MTORC1 and activates macroautophagy/autophagy.

Can HMGB1 inhibition reduce entrectinib-induced cardiotoxicity?

Yes. The study reports that HMGB1 inhibition prevents cardiotoxicity induced by entrectinib in both in vivo and in vitro models, with tanshinone IIA lowering HMGB1 protein levels.

Sep 28, 2026

Uploaded by SANS