BAX/MLKL signaling contributes to lipotoxicity-induced lysosomal membrane permeabilization in alcohol-associated liver disease.

ABSTRACT

Lysosomal membrane permeabilization (LMP) has emerged as a significant component of cellular signaling pathway by which autophagy or cell death is regulated under many pathological situations including alcohol-associated liver disease (ALD). However, the mechanisms involved in the regulation of LMP in ALD remain obscure. Recently, we demonstrated that lipotoxicity serves as a causal factor to trigger LMP in hepatocytes. We identified that the apoptotic protein BAX (BCL2 associated X, apoptosis regulator) could recruit MLKL (mixed lineage kinase domain-like pseudokinase), a necroptotic executive protein, to lysosomes and induce LMP in various ALD models. Importantly, the pharmacological or genetic inhibition of BAX or MLKL protects hepatocytes from lipotoxicity-induced LMP. Thus, our study reveals a novel molecular mechanism that activation of BAX/MLKL signaling contributes to the pathogenesis of ALD through mediating lipotoxicity-induced LMP.Abbreviations ALD alcohol-associated liver disease; BAX BCL2 associated X; LAMP2 lysosomal associated membrane protein 2; LMP lysosomal membrane permeabilization; MLKL mixed lineage kinase domain-like pseudokinase; PA palmitic acid.