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Volume 27
Issue 17
10.3390/ijms27177771
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury

by
Xiaowen Zhang
1,†,
Wenwei Li
1,†,
Luqi Li
1,
Ying Wang
1,
Wei Tang
1,
Jing Zhang
1,* and
Zichun Hua
1,2,3,*
1
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
2
Changzhou High-Tech Research Institute of Nanjing University, Changzhou 213164, China
3
Faculty of Pharmaceutical Sciences, Xinxiang Medical University, Xinxiang 453002, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(17), 7771; https://doi.org/10.3390/ijms27177771 (registering DOI)
Submission received: 9 July 2026 / Revised: 25 August 2026 / Accepted: 28 August 2026 / Published: 30 August 2026
(This article belongs to the Section Biochemistry)
Versions Notes

Abstract

Acetaminophen (APAP) represents a major cause of drug-induced liver injury (DILI), and effective pharmacological interventions remain limited. Annexin A5 (AnxA5), a Ca2+-dependent phospholipid-binding protein, participates in diverse biological processes related to tissue repair. In this study, we evaluated AnxA5 expression in APAP-challenged mouse livers and clinical samples from patients with liver injury. Using hepatic cell lines AML12 and HepG2, we performed overexpression-based functional assays to assess the cytoprotective effects of AnxA5 against APAP toxicity. Co-immunoprecipitation assays were applied to characterize protein interactions, and mitochondrial functional parameters were measured to dissect the underlying molecular mechanism. We found that AnxA5 was significantly upregulated in both APAP exposed mice and APAP DILI patients. Cellular functional assays showed that AnxA5 overexpression mitigated APAP triggered cytotoxicity in AML12 and HepG2 cells. Mechanistically, AnxA5 bound to voltage dependent anion channel 1 (VDAC1), restrained VDAC1 mediated mitochondrial Ca2+ influx, and suppressed VDAC1 oligomerization, which further inhibited mitochondrial permeability transition pore (mPTP) opening. In an APAP-induced liver injury mouse model, exogenous recombinant AnxA5 treatment maintained mitochondrial integrity and ameliorated hepatic inflammation and liver damage. Collectively, our data reveal AnxA5 as an endogenous mitochondrial protective factor and support its therapeutic potential against APAP-induced liver injury.
Keywords: liver injury; APAP toxicity; AnxA5; mitochondria; mPTP opening liver injury; APAP toxicity; AnxA5; mitochondria; mPTP opening

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MDPI and ACS Style

Zhang, X.; Li, W.; Li, L.; Wang, Y.; Tang, W.; Zhang, J.; Hua, Z. Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury. Int. J. Mol. Sci. 2026, 27, 7771. https://doi.org/10.3390/ijms27177771

AMA Style

Zhang X, Li W, Li L, Wang Y, Tang W, Zhang J, Hua Z. Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury. International Journal of Molecular Sciences. 2026; 27(17):7771. https://doi.org/10.3390/ijms27177771

Chicago/Turabian Style

Zhang, Xiaowen, Wenwei Li, Luqi Li, Ying Wang, Wei Tang, Jing Zhang, and Zichun Hua. 2026. "Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury" International Journal of Molecular Sciences 27, no. 17: 7771. https://doi.org/10.3390/ijms27177771

APA Style

Zhang, X., Li, W., Li, L., Wang, Y., Tang, W., Zhang, J., & Hua, Z. (2026). Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury. International Journal of Molecular Sciences, 27(17), 7771. https://doi.org/10.3390/ijms27177771

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