CO-mediated restoration of mitochondrial redox homeostasis contributes to alleviating multiple programmed cell deaths in hepatic I/R injury

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 Ca 2+ 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.