CO-mediated restoration of mitochondrial redox homeostasis contributes to alleviating multiple programmed cell deaths in hepatic I/R injury.
6 affiliations
- 1School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325027, China.
- 2Department of Neurosurgery, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. Electronic address: [email protected].
- 3Department of Gastroenterology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325024, China.
- 4Institute of Chemistry, University of Silesia in Katowice, Szkolna 9, Katowice, 40-006, Poland.
- 5Department of Gastroenterology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325024, China. Electronic address: [email protected].
- 6School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: [email protected].
Abstract
Hepatic ischemia-reperfusion injury (HIRI) remains a life-threatening complication in liver surgery and transplantation with no clinically approved therapy. Here we develop a hyaluronic acid-modified, ROS-responsive nanoformulation (CPs@HA) that enables controllable delivery of carbon monoxide (CO) specifically to injured liver tissue. We show that mitochondrial dysfunction is closely associated with three distinct cell death pathways (ferroptosis, cuproptosis, and disulfidptosis) that occur in parallel during HIRI. CPs@HA restores mitochondrial homeostasis through activating the AMPK-SIRT1-PGC-1α axis and restoring Ca²⁺ balance, accompanied by suppressed mtROS burst, preserved mitochondrial membrane potential (ΔΨm), maintained cristae ultrastructure, and restored respiratory complex (I & IV) and PDHC activities. This dual restoration of ATP energy supply and NADPH reducing capacity, together with the direct inhibitory effect of CO on oxidative stress and inflammation, is associated with the attenuation of ferroptosis, cuproptosis, and disulfidptosis, consistent with transcriptomics and functional assays in both hepatic tissues and cellular models. Consequently, CPs@HA effectively attenuates liver injury. By interrupting the vicious cycle of oxidative stress, metabolic collapse, and cell death with mitochondrial repair as a key component, this work suggests a potentially unified therapeutic strategy against HIRI and indicates that targeting mitochondrial homeostasis may help mitigate multiple cell death programs in parallel.
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BibTeX
@article{li2026comediated,
title = {{CO-mediated restoration of mitochondrial redox homeostasis contributes to alleviating multiple programmed cell deaths in hepatic I/R injury.}},
author = {Jiayu Li and Mengzhu Xu and Qiang Zhou and Hanjing Ni and Chengge Shi and Tianci Zuo and Lingjun Zhang and Hongyang Lu and Wei He and Li Yu and Quazi T H Shubhra and Changlong Xu and Xiaojun Cai},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104440},
url = {https://europepmc.org/article/MED/42900997},
note = {CC BY},
}
RIS
TY - JOUR
TI - CO-mediated restoration of mitochondrial redox homeostasis contributes to alleviating multiple programmed cell deaths in hepatic I/R injury.
AU - Jiayu Li
AU - Mengzhu Xu
AU - Qiang Zhou
AU - Hanjing Ni
AU - Chengge Shi
AU - Tianci Zuo
AU - Lingjun Zhang
AU - Hongyang Lu
AU - Wei He
AU - Li Yu
AU - Quazi T H Shubhra
AU - Changlong Xu
AU - Xiaojun Cai
PY - 2026
DA - 2026/10/15
JO - Redox biology
DO - 10.1016/j.redox.2026.104440
UR - https://europepmc.org/article/MED/42900997
AB - Hepatic ischemia-reperfusion injury (HIRI) remains a life-threatening complication in liver surgery and transplantation with no clinically approved therapy. Here we develop a hyaluronic acid-modified, ROS-responsive nanoformulation (CPs@HA) that enables controllable delivery of carbon monoxide (CO) specifically to injured liver tissue. We show that mitochondrial dysfunction is closely associated with three distinct cell death pathways (ferroptosis, cuproptosis, and disulfidptosis) that occur in parallel during HIRI. CPs@HA restores mitochondrial homeostasis through activating the AMPK-SIRT1-PGC-1α axis and restoring Ca²⁺ balance, accompanied by suppressed mtROS burst, preserved mitochondrial membrane potential (ΔΨm), maintained cristae ultrastructure, and restored respiratory complex (I & IV) and PDHC activities. This dual restoration of ATP energy supply and NADPH reducing capacity, together with the direct inhibitory effect of CO on oxidative stress and inflammation, is associated with the attenuation of ferroptosis, cuproptosis, and disulfidptosis, consistent with transcriptomics and functional assays in both hepatic tissues and cellular models. Consequently, CPs@HA effectively attenuates liver injury. By interrupting the vicious cycle of oxidative stress, metabolic collapse, and cell death with mitochondrial repair as a key component, this work suggests a potentially unified therapeutic strategy against HIRI and indicates that targeting mitochondrial homeostasis may help mitigate multiple cell death programs in parallel.
SN - 2213-2317
ER -