Adipose-derived mesenchymal stem cell exosomes ameliorate copper metabolism dysregulation and reduce cuproptosis caused by liver IRI.

INTRODUCTION

Hepatic ischemia reperfusion injury is an important pathological factor leading to complications after hepatectomy and transplantation. Although cuproptosis has been reported as a new paradigm of programmed death triggered by copper homeostasis imbalance, its regulatory mechanisms and intervention strategies in liver IRI remain to be fully elucidated. The purpose of this study was to reveal the role of cuproptosis in liver IRI, and to elucidate the molecular mechanism by which adipose-derived stem cell exosomes (ADSC-Exos) exert therapeutic effects by regulating copper metabolism.

METHODS

Rat IRI models were established to evaluate copper metabolism dysregulation and cuproptosis activation. Subsequently, miniature pig models underwent laparoscopic IRI induction to assess ADSC-Exos's effects on copper homeostasis restoration over 7 days post-injury.

RESULTS

We found that liver IRI disrupts copper homeostasis through a dual pathway: it inhibits membrane transporters CTR1 and ATP7B to affect copper ion excretion, and down-regulates intracellular copper chaperones ATOX1, CCS and COX17 expression, resulting in intracellular copper metabolism disorders. Excessive copper ions will bind to the lipoylated protein DLAT, induce its oligomerization and mitochondrial Fe-S cluster protein depletion, eventually leading to cuproptosis in hepatocytes and aggravating IRI. The intervention of ADSC-Exos can effectively regulate the disorder of copper metabolism in hepatocytes, inhibit the occurrence of cuproptosis, and reduce liver IRI.

DISCUSSION: This study first confirmed the damage mechanism of cuproptosis pathway caused by liver IRI, and revealed the regulatory mechanism of ADSC-Exos to hinder the process of cuproptosis by repairing the copper metabolism pathway of hepatocytes.