Sintilimab combined with acetaminophen aggravates liver injury through apoptotic and disturbed bile acid pathways

Abstract

Sintilimab, an immune checkpoint inhibitor, and acetaminophen (APAP), a common analgesic, have been implicated in hepatotoxicity. However, their combined effect on liver injury remains understudied. This study investigated the exacerbating hepatotoxic effects of sintilimab in combination with APAP in mice, focusing on the apoptotic markers and bile acids disruptions. We found that their combination significantly increased serum liver enzymes (aminotransferase and alanine aminotransferase), induced histological liver damage, and boosted hepatic oxidative stress markers (reactive oxygen species, 8-hydroxy-2’-deoxyguanosine, malondialdehyde) while depleting glutathione. Furthermore, the co-treatment also heightened apoptotic markers (cytochrome C, caspase-9, caspase-3, Bax) compared to the control and APAP group alone, indicating a more pronounced apoptotic response. Additionally, it downregulated CYP7A1 expression and disrupted bile acid metabolism, characterized by decreased levels of primary bile acids and increased levels of secondary bile acids, suggesting a role in the aggravated liver injury. This highlights the potential mechanism by which sintilimab and APAP interact, leading to increased oxidative stress, apoptosis and disruption of bile acid homeostasis, which together contribute to the exacerbation of liver injury. The study underscores the need for caution when co-administering sintilimab and APAP, emphasizing the importance of monitoring liver injury to mitigate the risk of combined drug use.