2481-P: Hepatocyte AADAC Attenuates MASLD-Driven Liver Fibrosis by Suppressing Profibrotic Exosome Release via Inhibiting Rab27a Palmitoylation

Introduction and Objective: AADAC is a hepatocyte-enzyme with unknown role in MASLD fibrosis. We investigated its function and mechanism in hepatocyte-stellate cell crosstalk. Methods: Human AADAC expression was analyzed in primary hepatocytes. Hepatocyte-specific Aadac knockout (KO) and overexpressing (OE) mice were fed HFHC diet. Exosomes were characterized from hepatocyte media. Molecular interactions and Rab27a palmitoylation were assessed. Fibrosis was evaluated histologically and biochemically. Results: 1) AADAC was downregulated in MASLD hepatocytes, correlating with fibrosis severity. 2) Aadac KO exacerbated, while OE ameliorated HFHC-induced liver fibrosis in mice. 3) AADAC loss increased hepatocyte exosome secretion, promoting HSC activation; exosome inhibition abrogated this effect. 4) Mechanistically, AADAC interacted with ACSL1, limiting palmitoyl-CoA production and subsequent Rab27a palmitoylation at C221. 5) Palmitoylation stabilized Rab27a, enhancing exosome release. 6) Restoring AADAC in established MASLD reduced Rab27a palmitoylation, exosome secretion, and fibrosis. Conclusion: Hepatocyte AADAC protects against MASLD fibrosis by suppressing pro-fibrotic exosome release via an ACSL1-palmitoyl-CoA-Rab27a palmitoylation axis, revealing a novel therapeutic target. Disclosure X. Xiao: None. Funding This systematically received funding from the National Natural Science Foundation of China (82070873, 82000813, 82470910), Hunan Provincial Health Commission's 2023 National Key Clinical Specialty Major Scientific Research Project (z2023051 and z2023066), Natural Science Foundation of Hunan province(2020JJ8097, 2021JJ40496, 2020SK51814) and Major special projects of Hunan provincial health and family planning commission (A2017011).