GDF11 mitigates liver injury associated with pancreatitis by inhibiting endoplasmic reticulum (ER) stress and the activation of the TXNIP/NLRP3 inflammasome.

Severe acute pancreatitis (SAP) is a severe inflammatory disease caused by pancreatic autodigestion. During its progression, systemic inflammatory response syndrome (SIRS) is triggered, which can lead to multiple organ dysfunctions. The liver, being a central metabolic organ and adjacent to the pancreas, is particularly vulnerable to damage during SAP and serves as a key hub for systemic complications. In SAP, pancreatic enzymes and inflammatory factors are released, attacking the liver, causing functional abnormalities, injury, and potentially leading to liver failure. However, the mechanisms underlying pancreatitis-associated liver injury (PALI) remain unclear, and there is a lack of effective treatments. Endoplasmic reticulum stress (ERS) is a critical pathological process caused by the imbalance of endoplasmic reticulum homeostasis. When cells are under continuous stress, the unfolded protein response (UPR) activates apoptotic programs, promoting inflammation and inducing programmed cell death. ERS is abnormally activated in mouse SAP models, making it a potential therapeutic target for PALI. In this study, Growth Differentiation Factor 11 (GDF11) exhibited therapeutic potential in liver diseases. We found that in SAP mice with liver injury, endogenous GDF11 expression in the liver decreased, while exogenous GDF11 improved the prognosis of pancreatitis-induced liver injury. Using the ERS inducer thapsigargin (TG), we demonstrated that exogenous GDF11 targets ERS to modulate SAP-induced liver injury, involving ERS - associated oxidative stress and apoptosis. Additionally, exogenous GDF11 mitigates SAP-related liver injury by targeting the ERS/TXNIP/NLRP3 axis to regulate inflammatory responses.