Acute liver failure-induced arginine deficiency impairs blood-brain barrier via inhibiting mTORC1-S6K1/4EBP1 pathway and inducing autophagy.

Blood-brain barrier (BBB) impairment plays a crucial role in the development of hepatic encephalopathy. Our previous work demonstrated that hepatic ischemia-reperfusion-induced acute liver failure (ALF) impairs the BBB by releasing arginase, but the underlying mechanism remains unclear. In this study, we discovered that ALF-induced arginase accumulation leads to arginine (Arg) deficiency, causing BBB cells to arrest in G1 phase. This arrest was associated with decreased expression of key cell cycle regulatory proteins, activation of autophagy, and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Silencing mTORC1 downstream protein p70 ribosomal protein S6 kinase 1 (S6K1) or eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) showed similar effects as Arg deficiency, while activating the mTORC1 pathway attenuated arginase-induced cell cycle delay. Furthermore, inhibition of autophagy with 3-methyladenine or silencing Beclin-1 partially reversed the arginase-induced effects. These in vitro findings were corroborated in rat models of ALF induced by thioacetamide or acetaminophen, as well as in rats treated with arginase, all of which exhibited elevated plasma arginase activity, reduced Arg levels, increased BBB permeability, and suppressed BBB cell proliferation. These changes were accompanied by alterations in markers related to cell cycles, mTORC1 signaling, and autophagy, which were reversible upon Arg supplementation. In summary, our research reveals that ALF-induced BBB damage is driven by Arg deprivation due to arginase release, leading to G1 phase arrest through mTORC1 pathway inhibition and autophagy induction, which provides new insights into the prevention and treatment of ALF-induced BBB damage and hepatic encephalopathy.