Abstract
Acute-on-chronic liver failure (ACLF) is an acute and severe syndrome with high mortality and limited therapeutic options. Excessive systemic inflammation, which drives hepatocyte dysfunction and programmed cell death, constitutes the hallmark feature of ACLF progression. PANoptosis, a coordinated form of apoptosis, necroptosis, and pyroptosis, has been implicated in ACLF pathogenesis, while its precise regulatory mechanisms remain elusive. Our previous studies have revealed the crosstalk between CD147 and systemic inflammation, while the specific function of CD147 in ACLF progression remains poorly characterized. This study was aimed to elucidate the role of CD147 in regulating PANoptosis during ACLF progression. Bioinformatics analysis indicated that PANoptosis activation was strongly correlated with inflammatory receptor CD147. Both mRNA and protein expression of CD147 were markedly upregulated in ACLF mice and patients. Moreover, CD147 blockade inhibited PANoptosis activation and alleviated liver injury in vivo, indicating a pivotal role of CD147 in driving ACLF progression. Using co-immunoprecipitation coupled with mass spectrometry, we identified S100A8/A9 as the top upregulated interacting partner of CD147, and elevated hepatic S100A8/A9 expression was further validated. In AML12 cells, S100A8/A9 combined with IFN-γ triggered hepatocyte PANoptosis in a CD147-dependent manner. Furthermore, S100A8/A9 combined with IFN-γ promoted the phosphorylation of p38 MAPK, HUWE1 expression, and K27-linked ubiquitination of AIM2, whereas these effects were suppressed by CD147 inhibition. Additionally, pharmacological inhibition of p38 MAPK effectively suppressed HUWE1 expression and PANoptosis activation. Collectively, our findings highlight that the elevated S100A8/A9 drives hepatocyte PANoptosis via CD147-p38 MAPK-HUWE1 axis, and exhibit potential as a promising therapeutic strategy for ACLF.