Role of copper ion overload triggered by CD44 endocytosis on STAT3-mediated cuproptosis in septic myocardial injury

Abstract Sepsis-induced myocardial injury (SIMI) is a severe complication in sepsis patients, contributing to high mortality rates. The pathogenesis remains unclear, but emerging evidence suggests copper ion overload may trigger cell death via "cuproptosis." This study investigates the role of CD44, a glycoprotein involved in inflammation and metal ion uptake, in copper-induced cell death in SIMI. Using an LPS-induced H9C2 cardiomyocyte model, we found CD44 expression upregulated in SIMI, correlating with increased copper levels and oxidative stress. CD44 inhibition reduced copper overload and mitigated cell damage, confirming its role in copper-mediated injury. Furthermore, CD44 facilitated copper uptake into mitochondria, inducing dysfunction via STAT3 pathway activation. STAT3 overexpression exacerbated myocardial injury, highlighting its critical role. These findings suggest CD44-mediated STAT3 activation contributes to copper overload and SIMI, positioning CD44 inhibition as a potential therapeutic strategy for sepsis-induced myocardial damage.