ROS-scavenging nanoparticles loaded with tectorigenin protect against acetaminophen-induced hepatotoxicity by interrupting the calcium/ROS-mediated pathogenic endoplasmic reticulum–Mitochondrial signaling cascade

Sep 29, 2026

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Acetaminophen (APAP) overdose is a leading cause of acute liver injury and acute liver failure worldwide, creating major clinical and public health burden due to rapid onset and high morbidity. Current treatment with N-acetylcysteine is time-dependent and prolonged regimens add side effects, while many natural hepatoprotective compounds face poor physicochemical and pharmacokinetic properties. Here, tectorigenin is encapsulated in a ROS-responsive nanoplatform (PBHB@Tec) that improves bioavailability, enables site-selective hepatoprotection, scavenges ROS, and triggers oxidative release. In APAP-induced ALI mice, PBHB@Tec reduces ER stress and ER Ca2+ leak, prevents mitochondrial Ca2+ overload, lowers mitochondrial ROS, restores antioxidant defenses, and disrupts a feedforward calcium/ROS apoptotic cascade.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

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Introduction

Bioactive Materials 58 (2026) 408–421 Contents lists available at ScienceDirect Bioactive Materials journal [homepage:](homepage: www.keaipublishing.com/en/journals/bioactive-materials)[ www.keaipublishing.com/en/journals/bioactive-materials](homepage: www.keaipublishing.com/en/journals/bioactive-materials) | ROS-scavenging nanoparticles loaded with tectorigenin protect against acetaminophen-induced hepatotoxicity by interrupting the calcium/ ROS-mediated pathogenic endoplasmic reticulum–Mitochondrial signaling cascade | | | | | --- | --- | --- | --- | | Yaqi Zhang a,b,1, Zeyuan Jinc,1, Lvwan Xu a,b, Zilong Zhong c, Xinyu Wang a,b, Changyou Gao c,d,e,f,*, Lanjuan Li a,b,**
a State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
b Yuhang Institute of Medical Science Innovation and Transformation, Hangzhou, 311112, China
c MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China
d Zhejiang Engineering Research Center for Interface Technology of Medical Polymers and Devices, Shaoxing Key Laboratory of Healthcare Materials and Application Technology, and Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing, 312099, China
e The State Key Laboratory of Transvascular Implantation Devices, Zhejiang University, Hangzhou, 310009, China
f Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China | | | | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords:
Acute liver injury
Reactive oxygen species Endoplasmic reticulum stress Mitochondrial dysfunction Tectorigenin | | Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI) and acute liver failure (ALF) worldwide, representing a major clinical and public health challenge due to its rapid onset and high morbidity. Current clinical treatment is limited to N-acetylcysteine (NAC), but its efficacy is highly time-dependent and the prolonged regimen imposes additional clinical burdens and side effects. Natural compounds hold tremendous promise for hepatoprotection, but their clinical translation is limited by unfavorable physicochemical and pharmacokinetic properties. In this study, tectorigenin (Tec), an isoflavone possessing anti-inflammatory and antioxidative activity, was encapsulated within a reactive oxygen species (ROS)-responsive nanoplatform (PBHB@Tec) to enhance bioavailability and enable site-selective hepatoprotection. PBHB@Tec possessed diameters compatible with passage through hepatic sinusoidal fenestrae into the space of Disse enabling direct hepatocyte interaction, while exhibiting potent ROS scavenging activity and undergoing ROS-triggered morphological degradation that accelerated Tec release under oxidative conditions. In an APAP-induced ALI mouse model, PBHB@Tec markedly attenuated ALI phenotypes. Mechanistically, PBHB@Tec reduced endoplasmic reticulum (ER) stress, which alleviated ER Ca2+ leak and subsequently prevented mitochondrial Ca2+ overload. This, in turn, lowered mitochondrial ROS production and restored antioxidant defenses, collectively disrupting the feedforward calcium/ROS apoptotic cascade. These broad improvements in ER-mitochondrial homeostasis positioning PBHB@Tec as a promising ROS-responsive nanotherapy for APAP-induced hepatotoxicity. | | Peer review under the responsibility of editorial board of Bioactive Materials. * Corresponding author. MOE Key Laboratory of Macromolecular Synthesis and Functio

FAQs

Why is acetaminophen overdose particularly dangerous clinically?

Acetaminophen overdose is a leading cause of acute liver injury and acute liver failure, characterized by rapid onset and high morbidity worldwide.

What limitation affects current clinical treatment for acetaminophen-induced liver injury?

N-acetylcysteine efficacy is highly time-dependent, and prolonged regimens impose additional clinical burdens and side effects.

How does PBHB@Tec mechanistically protect against acetaminophen-induced hepatotoxicity?

PBHB@Tec reduces endoplasmic reticulum stress, alleviates ER Ca2+ leak, prevents mitochondrial Ca2+ overload, lowers mitochondrial ROS production, restores antioxidant defenses, and interrupts a calcium/ROS apoptotic feedforward cascade.

Sep 29, 2026

Uploaded by Cipher