Histone Succinylation-Driven LINE-1 Reactivation Links High-Fat Diet Stress to Hepatic Inflammation and Liver Disease

Abstract

Endogenous retroelements such as LINE-1 (L1) are stress-responsive genomic elements increasingly implicated in stress induced inflammation and associated pathogenic states. Here, we uncover a novel mechanism whereby high-fat diet-associated palmitic acid stress triggers chromatin remodeling that derepresses L1 elements and an IRF3-dependent interferon response, leading to innate immune activation in hepatocytes. Mechanistically, we show that that palmitic acid exposure promoted p300/CBP-mediated H3K122 succinylation at L1 promoters, coupled with reduced sirtuin desuccinylase cofactor availability, thereby enhancing chromatin accessibility and transcription. Antisense oligonucleotide-mediated L1 silencing abrogated this response by resetting chromatin homeostasis, demonstrating a causal role for L1 in palmitate-induced inflammation. In vivo, L1 knockdown in a fructose-palmitate-cholesterol (FPC) diet-induced mouse model of MASLD/MASH improved insulin sensitivity, reduced hepatic inflammation, and ameliorated fibrosis. These findings identify L1 derepression as a key epigenetic and inflammatory effector of dietary lipid stress and establish L1 inhibition as a potential therapeutic strategy for metabolic liver disease.